Synthesis of chroman derivatives by the ring expansion reaction of spirodienones, and an assessment of their plant growth inhibition

Article abstract of DOI:10.1246/bcsj.77.2257

Lewis acid-promoted 1,2-shift rearrangement reactions of the spirodienones, generated by the anodic oxidation of phenol derivatives, provided corresponding chromans. In addition to steric repulsion, electron-donating or withdrawing characteristics of the

Full text of DOI:10.1246/bcsj.77.2257

ꢀ 2004 The Chemical Society of Japan
Bull. Chem. Soc. Jpn., 77, 2257–2263 (2004) 2257
Synthesis of Chroman Derivatives by the Ring Expansion Reaction
of Spirodienones, and an Assessment of their Plant Growth Inhibition
Fuminao Doi, Taiga Ohara, Takahisa Ogamino, Keiko Higashinakasu,1
ꢀ
Koji Hasegawa,1 and Shigeru Nishiyama
Department of Chemistry, Faculty of Science and Technology, Keio University,
Hiyoshi 3-14-1, Kohoku-ku, Yokohama 223-8522
1Institute of Applied Biochemistry, University of Tsukuba, Tennoudai 1-1-1, Tsukuba 305-0044
Received July 22, 2004; E-mail: nisiyama@chem.keio.ac.jp
Lewis acid-promoted 1,2-shift rearrangement reactions of the spirodienones, generated by the anodic oxidation of
phenol derivatives, provided corresponding chromans. In addition to steric repulsion, electron-donating or withdrawing
characteristics of the arylic substituents controlled the direction of the rearrangements. The plant growth inhibitory ac-
tivity of several chroman derivatives was evaluated. In contrast to apparent inhibitions of 21c and 22c against both cress
and oat, the selective activity against coleoptile and root of oat was observed in 21a, 21b, and 22d. Interestingly, the
regioisomer 22b of 21b showed no activity.
During our extensive electrochemical approach towards the
synthesis of a wide range of biologically active substances,1 it
was observed that the spirodienone derivative 2, generated by
anodic oxidation of the corresponding monobromophenol 1,
the same methyl substitution as that of heliannuol E, the phe-
nol derivatives carrying a bromine substituent (type-5), which
was considered to regulate the oxidation potential as well as
the reaction-mode,1 was employed for the synthesis of natural
products.4 In addition, despite its low yield, treatment of 8 with
was converted under BF3 OEt2 conditions into chromans 3
ꢁ
and 4 (Scheme 1).2 To apply this series of anodic oxidation
and the following 1,2-rearrangement reactions to the synthesis
of heliannuol E, an allelochemical of sunflower, Helianthus
annuus L. cv.,3 the bromomethyl and methyl derivatives, 5
and 6, were submitted to anodic oxidation. Whereas 6 provid-
ed the spiro compound 8 in 20% yield, the bromo-spiro deriv-
ative 7 was produced in 50% yield, and the following rear-
rangement gave a mixture of 9 and 11 in 33 and 6% yields, re-
spectively.4a Based on a preferential production of 9 carrying
BF3 OEt2 underwent high rearrangement selectivity to give
the corresponding chromans 10 in 62% yield,5 as well as a
trace amount of 12.6
ꢁ
At the outset, the direction of this rearrangement reaction
(ex. 2 ! 3, 4) was considered to be the opposite side of such
bulky substituents as methyl and bromo groups to avoid steric
repulsion.2b However, as mentioned above, the ratio of the
chroman-isomers produced, depended on the substituents at
the ortho positions of the phenol groups; the methyl derivative
O
+
–
HO
Br
O
- 2 e , - H
+
OH
OH
Br
Br
O
1
2
Br
HO
Br
•
HO
BF OEt
3
2
+
HO
Me
O
O
4
3
O
OH
Heliannuol E
R
R
R
Me
O
HO
Me
HO
Me
HO
+
OH
Me
O
R
O
O
11: R = Br
12: R = H
7: R = Br
8: R = H
5: R = Br
6: R = H
9: R = Br
10: R = H
Scheme 1. Synthesis of the spirodienones, and its conversion into the chroman derivatives.
Published on the web December 10, 2004; DOI 10.1246/bcsj.77.2257

2258 Bull. Chem. Soc. Jpn., 77, No. 12 (2004)
Chemistry and Activity of Chroman Derivatives
8 provided 10 with high selectivity, while a nearly equal prod-
ꢂ
ture) was observed in the case of the bromophenol 1.2b To un-
derstand the perspective of the rearrangement to the chroman
Results and Discussion
uct distribution (3/4 = 3:2 at 0 C, ca. 1:1 at room tempera-
Spirodienones 20a–e, substrates for the rearrangement ex-
amination, were synthesized by the anodic oxidation of the
corresponding phenols, 15a–e. The phenol derivative carrying
a methyl substituent 15a was produced from the known alde-
hyde 137 by a carbon-chain elongation reaction, and concom-
itant hydrogenolysis (148) and halogenation at an appropriate
step (Scheme 2). Trifluoromethyl and fluoro derivatives
(15b, 15c, and 15d) were prepared by essentially the same pro-
cedure as in the case of 15a, starting from 16 through its benz-
aldehyde derivative, obtained by reduction of 17,9 and from
18.10 The chlorine derivative 15e was produced from 19.11
When 15a was submitted to constant current electrolysis
conditions (30 mA, 3.0 F/mol in MeNO2), the spirodienone
20a was produced in 51% yield (Table 1). Although the oxida-
tion of 15a and 15e gave the corresponding spirodienones in
moderate yields, 15b, 15c, and 15d provided 20b, 20c, and
derivatives under the BF3 OEt2 conditions, the effect of sub-
ꢁ
stituents should be inspected by utilizing several spirodienones
synthesized from the p-(3-hydroxypropyl)phenol derivatives.
In a previous paper,5 we assessed the plant growth inhibitory
activity of heliannuol congeners possessing chroman or ben-
zooxepin skeletons. Among them, 9–11 carrying relatively sim-
ple or bromine-containing structures, exhibited activities in
10ꢃ3–10ꢃ4 M (1 M = 1 mol dmꢃ3) concentrations against hy-
pocotyl and the root of cress, as well as coleoptile and the root
of oat. Against such a background, several chromans synthe-
sized in this investigation were submitted to biological assess-
ments to acquire further structure–activity relationships of the
growth-inhibitory activity of the chroman derivatives against
cress and oat. We describe herein the investigation process.
Cl
BnO
HO
1. SO Cl
2
2
1. Wittig reaction
HO
Me
2. LiAlH
4
Me
2. H , 10% Pd/C
CHO
2
Me
OH
COOMe
13
16
14
15a
X
1. Br
2
HO
BnO
HO
1. DIBAL-H
2. Wittig reaction
3. H , 10% Pd/C
2. K CO , BnBr
2
3
OH
F C
3
F C
3
CN
3. CuCN
F C
3
17
2
15b X= H
15c X= Br
•
Pyr HBr
3
4. LiAlH
4
BnO
F
1. Heck reaction
HO
F
HO
Cl
2. H , 10% Pd/C
2
OH
OR
Br
3. LiAlH4
19 R= Ac
15e R= H
18
15d
K CO
2
3
Scheme 2. Synthesis of 15a–15e.
Table 1. Synthesis of the Spirodienones 20a–20e
Entry
Compound
R
X
ConditionaÞ
Yield/%
1
2
5
6
Me
Me
Br
H
CCE
CCE
7
8
78bÞ
36bÞ
3
4
5
6
7
8
9
10
15a
15b
Me
Cl
H
CCE
CCE
PIFA
CCE
PIFA
CCE
PIFA
CCE
20a
20b
51
4
CF3
47
38
65
35
61
68
15c
CF3
Br
20c
15d
H
H
F
20d
20e
15ecÞ
Cl
a) In CCE conditions, MeNO2 (solvent) and n-Bu4NClO4 as supporting salts were used. b) Upon
using dioxane–60% aq HClO4 for 5 and acetone for 6 as solvents, 7 and 8 were obtained in 50
(Ref. 4a) and 20% (Ref. 5) yields, respectively. c) Ref. 11.
R
R
O
[O]
HO
X
X
OH
O
15
20

F. Doi et al.
Table 2. Synthesis of the Chromans
Bull. Chem. Soc. Jpn., 77, No. 12 (2004) 2259
EntryaÞ
Compound
R
X
Temperature
Time
Yield/%
(Product ratio)
1
2
3
4
5
6
20a
20b
Me
CF3
Cl
H
rt
rt
reflux
rt
rt
rt
1.5 h
1 h
3 h
2 d
20 min
25 min
21a/22a
21b/22b
42 (2:1)
quant (1:2.3)
65 (1:2.6)
74 (1:1.5)
63 (0:1)
20c
CF3
Br
21c/22c
20d
20e
H
H
F
Cl
21d/22d
21e/22e
59 (1:9)
7
8
7
8
Me
Me
Br
H
rt
rt
3 h
20 min
9/11
10/12
39 (5:1)cÞ
62 (1:trace)dÞ
a) CH2Cl2 was used as a reaction solvent. b) The ratios were determined by comparison of integrations of
1
the H NMR spectra. c) Ref. 4a. d) Ref. 5.
R
X
R
O
X
HO
R
HO
X
+
O
O
O
20a-e
21a-e
22a-e
Table 3. Inhibitory Activity of the Chroman Derivatives on the Growth of Cress and Oat Seedlings
EC50aÞ/M
Cress
Oat
Compounds
Hypocotyl
Root
Coleoptile
Root
6:8 ꢅ 10ꢃ3
21a
21b
21c
22b
22c
1:0 ꢅ 10ꢃ3
7:5 ꢅ 10ꢃ4
9:9 ꢅ 10ꢃ4
—
9:0 ꢅ 10ꢃ4
1:2 ꢅ 10ꢃ3
8:4 ꢅ 10ꢃ4
7:0 ꢅ 10ꢃ4
1:0 ꢅ 10ꢃ3
2:9 ꢅ 10ꢃ3
—
1:8 ꢅ 10ꢃ3
9:0 ꢅ 10ꢃ4
1:5 ꢅ 10ꢃ3
>10ꢃ2
8:0 ꢅ 10ꢃ3
2:6 ꢅ 10ꢃ3
>10ꢃ2
—
1:5 ꢅ 10ꢃ3
—
1:0 ꢅ 10ꢃ3
2:9 ꢅ 10ꢃ3
1:3 ꢅ 10ꢃ3
>10ꢃ2
22d
(ꢄ)-Heliannuol E
—
8:2 ꢅ 10ꢃ4
a) EC50 represents the concentration of samples, which cause 50% inhibition of the shoot and
root growth of cress or oat seedlings, respectively. — No activity.
20d in 4, 38, and 35% yields, respectively. On the other hand,
the bis(trifluoroacetoxy)iodobenzene (PIFA) oxidation of 15b–
d provided 20b–d in acceptable yields, while a sufficient yield
was not obtained under anodic oxidation conditions.
1:1 (3/4)2b and 1:9 (21e/22e) mixtures (entry 6). Accordingly,
the effectiveness of the electron-donation was in the order of
the electron negativity, F > Cl > Br. The electron-withdraw-
ing property of a trifluoromethyl group gave 22b and 22c as
major products, although the rearrangement rate slowed down
upon having a bromine substituent (20c).
Transformation of 20a–e into chromans 21a–e and 22a–e
under BF3 OEt2 conditions was carried out (Table 2). In the
ꢁ
case of the trifluoromethyl derivatives, 20b and 20c were pref-
erentially rearranged to the trifluoromethyl-side (22b, 22c),
which was sterically more hindered moiety. This observation
indicated that the reaction was modulated by an apparent elec-
tron-withdrawing effect of the trifluoromethyl group, rather
than its steric hindrance. In contrast, 20d carrying a fluorine-
substituent, was predominantly converted into 22d. The fluo-
rine-substituent might not play an electron-withdrawing part,
but an electron-donating part by the resonance effect.
Biological Assessment of Chroman Derivatives. A bio-
logical assay of the chroman derivatives synthesized in this in-
vestigation was performed (Table 3). Owing to good inhibitory
activity of the brominated chroman derivatives against both
cress and oat in a precedent investigation,5 other related deriv-
atives, particularly fluorine-containing derivatives, were ex-
pected to have effective activity for its similar atomic size to
that of hydrogen atom and strong electron negativity. As can
be seen in Table 3, while 22b showed no activity, compounds
21a–c, 22c, and 22d exhibited inhibitory activity against hypo-
cotyls and root of cress at 10ꢃ3–10ꢃ4 M concentration (EC50),
which was similar to that of (ꢄ)-heliannuol E.5 Comparing
21b with 22b, the position of the trifluoromethyl group might
contribute to the inhibitory effect; 22b carrying the trifluoro-
methyl group at C5, showed no activity, whereas substitution
at C7 (21b) provided inhibitory activity against cress, as well
as coleoptile of oat. Although 21b and 22d inhibited both hy-
pocotyl and root of cress, 21b exhibited no activity against root
As observed in the case of 7 and 8,4a,5 rearrangement of 20a
was conducted to avoid bulky methyl groups, leading to 21a.
Chloro- and bromo-substituents of the methyl phenols inter-
fered with the predominant production of 21a and 9 by the
electron-donating effect, which caused longer reaction times
(entries 1 and 7) than in the case of 10 (entry 8). The fluo-
rine-substituent of 20d exhibited strong electron donation to
provide 22d as a sole product, whereas 2 having a bromine
atom (rt, 15 min),2b and 20e possessing a chlorine, provided

2260 Bull. Chem. Soc. Jpn., 77, No. 12 (2004)
Chemistry and Activity of Chroman Derivatives
Na2S2O3, and brine. The organic layer was dried (Na2SO4), and
evaporated. A mixture of the residue, K2CO3 (5.3 g, 38 mmol)
and BnBr (2.28 mL, 19 mmol) in DMF (30 mL) was stirred at
room temperature for 21 h. The mixture was diluted with H2O
at 0 ꢂC, and extracted with EtOAc–hexane (1/1). The organic lay-
er was washed with brine, dried (Na2SO4), and evaporated. The
crude oil was chromatographed on a silica-gel short column (hex-
ane–EtOAc 60/1), and the product was immediately submitted to
the next reaction.
of oat, and no inhibition against coleoptile was detected in the
case of 22d. However, 21c, possessing a brominated structure
of 21b, recovered inhibition against root of oat. A direct com-
parison of the inhibitory activity between trifluoromethyl and
methyl derivatives has not been performed. However, upon re-
ferring to previous data,5 brominated derivatives 21c and 22c
inhibited all parts of cress and oat, similar to the case of 9
and 11, whereas the inactivity of 10 against coleoptile showed
different selectivity from that of 21b.
In conclusion, we identified that a dienone–phenol rear-
rangement was conducted, not only by the steric hindrance,
but also by both electron-donating and withdrawing effects.
In addition, a biological assay of several chroman derivatives
indicated that trifluoro compounds 21c and 22c evenly inhibit-
ed both cress and oat; however no activity of 21b against root
of oat, and low inhibition of 21a against coleoptile were ob-
served. Despite of a structural similarity to 21b, 22b showed
no activity. Further investigation is in progress.
To a solution of the benzyl ether in DMF (65 mL) wasꢂadded
CuCN (6.02 g, 67 mmol); the mixture was stirred at 130 C for
26 h. After the addition of H2O (75 mL), aqueous NH3 (70
ꢂ
mL), Et2O (70 mL), and EDTA (2.86 g, 7.7 mmol) at 0 C, the
mixture was stirred at room temperature for 20 h. The resultant
mixture was diluted with H2O, and washed with hexane–EtOAc
(1/1). The organic layer was washed with brine, dried (Na2SO4),
and evaporated. The crude mixture was chromatographed on a
silica-gel column (hexane–EtOAc 12/1 to 8/1) to afford 17
(26.5 g, 62%, 3 steps): mp 114.5–115 ꢂC (needles, EtOAc–hex-
ane); IR (KBr) 3080, 2227, 1618, 1508, 1335, 1288, 1130,
Experimental
1
1059, 1022 cmꢃ1; H NMR ꢀ 5.27 (2H, s), 7.11 (1H, d, J ¼ 8:3
General. All of the melting points were obtained on a Yanaco
MP-S3 melting-point apparatus and were uncorrected. IR spectra
were recorded on a JASCO Model A-202 spectrophotometer.
1H NMR and 13C NMR spectra were obtained on JEOL JNM
EX-270 and JEOL JNM GX-400 spectrometers in deuteriochloro-
form (CDCl3) using tetramethylsilane as an internal standard, un-
less otherwise stated. High-resolution mass spectra were obtained
on a Hitachi M-80 B GC–MS spectrometer operating at the ioni-
zation energy of 70 eV. Preparative and analytical TLC were car-
ried out on silica-gel plates (Kieselgel 60 F254, E. Merck A. G.,
Germany) using UV light and/or 5% molybdophosphoric acid
in ethanol for detection. Kanto silica-gel 60N (spherical. neutral,
63–210 mm) was used for column chromatography. Elemental
analyses were obtained on an ELEMENTAR Vario EL CHNS ap-
paratus. All anodic oxidation was conducted using a glassy carbon
beaker as an anode, a platinum wire as a cathode, and a standard
calomel electrode as a reference electrode.
Hz), 7.34–7.75 (5H, complex), 7.76 (1H, broad d, J ¼ 8:3 Hz),
7.89 (1H, broad s); 13C NMR ꢀ 70.8, 104.0, 113.9, 117.7, 120.4
(q, J ¼ 31:5 Hz), 122.3 (q, J ¼ 271:6 Hz), 126.7, 128.4, 128.7,
131.3 (q, J ¼ 5 Hz), 134.7, 137.4, 159.4; HRMS found m=z
277.0707, calcd for C15H10NF3O: M, 277.0713.
Synthesis of 4-(3-Hydroxypropyl)-2-(trifluoromethyl)phenol
(15b): To a solution of 17 (2.47 g, 11 mmol) in PhMeꢂ(70 mL)
was added DIBAL-H (1.01 M in PhMe, 20 mL) at ꢃ78 C under
an argon atmosphere; the mixture was stirred at ꢃ78 ꢂC for 15
min. The reaction was quenched by the addition of 6 M HCl,
ꢂ
and warmed up to 0 C. After 15 min, the mixture was extracted
with EtOAc. The organic layer was washed with sat. aq. NaHCO3
and brine, dried (Na2SO4), and then evaporated. The crude oil was
chromatographed on a silica-gel column (hexane–EtOAc 8/1 to
ꢂ
3/1) to afford an aldehyde (2.05 g, 82%): mp 81.5–82.5 C (nee-
dles, EtOAc–hexane): IR (NaCl) 3066, 2806, 1687, 1614, 1500,
1441, 1277, 1196, 1134 cmꢃ1 1H NMR ꢀ 5.29 (2H, s), 7.16
;
Synthesis of 6-Chloro-4-(3-hydroxypropyl)-2-methylphenol
(15a): A mixture of 14 (252 mg, 1.4 mmol) and SO2Cl2 (0.5
mL, 6.3 mmol) in CHCl3 (5 mL) was stirred at room temperature
for 6 h. The reaction was quenched by the addition of sat. aq.
NaHCO3 at 0 ꢂC, and extracted with EtOAc. The organic layer
was washed with brine, dried (Na2SO4), and evaporated. A solu-
tion of the residue in THF (4 mL) was slowly added to a solution
of LiAlH4 (100 mg, 2.6 mmol) in THF (4 mL) at 0 ꢂC; the mixture
was stirred for 15 min. The reaction mixture was diluted with
EtOAc, and the organic layer was washed with 6 M HCl, sat.
aq. NaHCO3 and brine, then dried (Na2SO4). After evaporation,
the residue was chromatographed on a silica-gel column (hex-
ane–EtOAc 4/1) to afford 15a (251.1 mg, 89%) as an oil: IR
(1H, d, J ¼ 8:8 Hz), 7.32–7.44 (5H, complex), 8.00 (1H, dd,
J ¼ 1:2, 8.8 Hz), 8.13 (1H, d, J ¼ 1:2 Hz), 9.91 (1H, s); 13C NMR
ꢀ 70.7, 113.3, 119.9 (q, J ¼ 31:4 Hz), 122.9 (q, J ¼ 271:7 Hz),
126.7, 128.3, 128.7, 129.0, 129.2 (q, J ¼ 4:9 Hz), 134.9, 135.0,
160.8, 189.5; HRMS found m=z 280.0684, calcd for C15H11F3O2:
M, 280.0709.
To a solution of the aldehyde (1.61 g, 7.1 mmol) in dry THF
(16 mL) was added Ph3P=CHCOOMe (4.8 g, 14 mmol) at room
temperature; the mixture was stirred for 6 h. The mixture was
warmed up to 55 ꢂC and stirred for an additional 12 h. After evap-
oration, the residue was purified by silica-gel column chromatog-
raphy (hexane–EtOAc 4/1) to afford an ester (1.94 g, 81%): mp
104.5–105 ꢂC (needles, hexane–EtOAc); IR (KBr) 3041, 2952,
1
(NaCl) 3365, 2943, 1487, 1327, 1120, 1051 cmꢃ1
;
1H NMR ꢀ
1709, 1637, 1614, 1508, 1438, 1385, 1340, 1282 cmꢃ1; H NMR
1.83 (2H, tt, J ¼ 6:6, 7.8 Hz), 2.25 (3H, s), 2.58 (2H, t, J ¼ 7:8
Hz), 3.66 (2H, t, J ¼ 6:6 Hz), 6.86 (1H, d, J ¼ 1:2 Hz), 6.99
(1H, d, J ¼ 1:2 Hz); 13C NMR ꢀ 16.4, 31.0, 34.2, 62.0, 119.2,
125.6, 125.8, 129.6, 134.0, 147.5; HRMS found m=z 200.0622,
calcd for C10H1335ClO2: M, 200.0604. Found: C, 59.70; H,
6.48%. Calcd for C10H13ClO2: C, 59.86; H, 6.53%.
Synthesis of 4-Phenylmethoxy-3-(trifluoromethyl)benzoni-
trile (17): A mixture of 16 (3.12 g, 19 mmol) and Br2 (0.99
mL, 19 mmol) in CHCl3 (50 mL) at room temperature was stirred
for 2.5 h. The resultant mixture was washed with H2O, sat. aq.
ꢀ 3.80 (3H, s), 5.24 (2H, s), 6.36 (1H, d, J ¼ 16:4 Hz), 7.04 (1H,
d, J ¼ 8:4 Hz), 7.33–7.44 (5H, complex), 7.61 (1H, dd, J ¼ 2, 8.4
Hz), 7.64 (1H, d, J ¼ 16:4 Hz), 7.77 (1H, d, J ¼ 2 Hz); 13C NMR
ꢀ 51.8, 70.4, 113.5, 117.1, 119.7 (q, J ¼ 30:5 Hz), 123.2 (q, J ¼
270:6 Hz), 126.7, 126.8 (q, J ¼ 5 Hz), 128.1, 128.6, 132.9, 135.6,
142.9, 157.6 (q, J ¼ 1:6 Hz), 167.1; HRMS found m=z 336.0960,
calcd for C18H15F3O3: M, 336.0972.
A mixture of the ester (1.78 g, 5.3 mmol) and a catalytic
amount of 10% Pd/C in MeOH (30 mL) was stirred at room tem-
perature for 5 h under a hydrogen atmosphere. After filtration, the

F. Doi et al.
Bull. Chem. Soc. Jpn., 77, No. 12 (2004) 2261
filtrate was evaporated, and the residue was chromatographed on a
silica-gel column (hexane–EtOAc 3ꢂ/1 to 2/1) to afford a phenol
(1.66 g, 92%, 2 steps): mp 91.5–92 C (needles, hexane–EtOAc);
IR (KBr) 3376, 2958, 1709, 1624, 1525, 1444, 1333, 1211, 1182
g, 98%), as an oil: 1H NMR ꢀ 2.60 (2H, t, J ¼ 6:8 Hz), 2.87
(2H, t, J ¼ 6:8 Hz), 3.67 (3H, s), 6.85–6.94 (3H, complex);
13C NMR ꢀ 30.0, 35.7, 51.8, 115.3 (d, J ¼ 17:3 Hz), 117.1,
124.3 (d, J ¼ 3:3 Hz), 133.2, 141.8 (d, J ¼ 14 Hz), 150.7 (d, J ¼
236:0 Hz), 173.3.
1
cmꢃ1; H NMR ꢀ 2.62 (2H, t, J ¼ 7:8 Hz), 2.91 (2H, t, J ¼ 7:8
Hz), 3.68 (3H, s), 5.77 (1H, broad s), 6.85 (1H, d, J ¼ 2 Hz),
7.25 (1H, dd, J ¼ 2, 8.3 Hz), 7.33 (1H, d, J ¼ 2 Hz); 13C NMR
ꢀ 29.9, 35.7, 51.9, 116.4 (q, J ¼ 30:6 Hz), 117.6, 123.9 (q, J ¼
271:7 Hz), 126.2 (q, J ¼ 4:9 Hz), 132.0, 133.2, 152.4 (q, J ¼
1:6 Hz), 173.8; HRMS found m=z 248.0705, calcd for
C11H11F3O3: M, 248.0751.
A mixture of the phenol and LiAlH4 (273.2 mg, 7.2 mmol) in
THF (40 mL) was stirred at room temperature for 15 min. The re-
action mixture was diluted with 6 M HCl, and extracted with
EtOAc. The organic layer was washed with sat. aq. NaHCO3
and brine, dried (Na2SO4), and evaporated. The residue was chro-
matographed on a silica-gel column (hexane–EtOAc 2/1) to af-
ford 15d (0.44 g, quant.) as an oil: IR (NaCl) 3323, 2499, 1520,
A mixture of the phenol (1.08 g, 4.4 mmol) and LiAlH4 (0.5 g,
13 mmol) in THF (40 mL) was stirred at room temperature for 25
min. The mixture was diluted with EtOAc (150 mL), washed with
6 M HCl, sat. aq. NaHCO3 and brine. The organic layer was dried
(Na2SO4) and evaporated. The residue was chromatographed on
a silica-gel column (hexane–EtOAc 1/1) to afford 15b (0.91 g,
95%): mp 119.5–121 ꢂC (needles, hexane–EtOAc); IR (NaCl)
1
1286 cmꢃ1; H NMR ꢀ 1.85 (2H, tt, J ¼ 7:3, 7.8 Hz), 2.63 (2H,
t, J ¼ 7:8 Hz), 3.68 (2H, t, J ¼ 7:3 Hz), 6.83–6.93 (3H, complex);
13C NMR ꢀ 31.1 (d, J ¼ 1:6 Hz), 34.1, 62.1, 115.3 (d, J ¼ 17:4
Hz), 117.0 (d, J ¼ 2:5 Hz), 124.4 (d, J ¼ 3:3 Hz), 134.5 (d, J ¼
5:7 Hz), 141.5 (d, J ¼ 14:2 Hz), 150.8 (d, J ¼ 236 Hz); HRMS
found m=z 170.0738, calcd for C9H11FO2: M, 170.0742.
1
3464, 2956, 1624, 1520, 1448, 1325, 1205, 1117 cmꢃ1; H NMR
Synthesis of 2-Chloro-4-(3-hydroxypropyl)phenol (15e): A
(CD3OD) ꢀ 1.78 (2H, tt, J ¼ 6:4, 7.6 Hz), 2.62 (2H, t, J ¼ 7:6
Hz), 3.54 (2H, t, J ¼ 6:4 Hz), 4.90 (1H, broad s), 6.84 (1H, d, J ¼
8:4 Hz), 7.21 (1H, dd, J ¼ 2, 8.4 Hz), 7.30 (1H, d, J ¼ 2 Hz);
13C NMR (CD3OD) ꢀ 32.0, 35.5, 62.0, 117.6, 117.6 (q, J ¼
29:8 Hz), 125.5 (q, J ¼ 270 Hz), 127.2 (q, J ¼ 5 Hz), 133.8,
134.1, 155.0 (q, J ¼ 1:6 Hz); HRMS found m=z 220.0712, calcd
for C10H11F3O2: M, 220.0710.
mixture of 1911 (109 mg, 0.48 mmol) and K2CO3 (668 mg, 4.8
mmol) in MeOH (5 mL) was stirred at room temperature for 12
h. After extraction, the crude product was chromatographed on
a silica-gel column (hexane–EtOAc 1/1) to afford 15e (81.8
mg, 92%): mp 78.5–80 C (needles, EtOAc–hexane); IR (NaCl)
3359, 2935, 1610, 1217, 1053 cmꢃ1 1H NMR (CD3COCD3) ꢀ
;
1.77 (2H, tt, J ¼ 6:4, 7.6 Hz), 2.59 (2H, t, J ¼ 7:6 Hz), 3.56
(2H, t, J ¼ 6:4 Hz), 3.75 (1H, broad s), 6.90 (1H, d, J ¼ 8:4
Hz), 6.99 (1H, dd, J ¼ 2:4, 8.4 Hz), 7.16 (1H, d, J ¼ 2:4 Hz),
8.51 (1H, broad s); 13C NMR (CD3COCD3) ꢀ 31.5, 35.3, 61.5,
117.3, 120.5, 128.6, 130.2, 135.5, 151.5; HRMS found m=z
186.0404, calcd for C9H1135ClO2: M, 186.0447.
Procedure of Anodic Oxidation: A solution of 5 (44.8 mg,
0.27 mmol) in MeNO2 (135 mL) in the presence of n-Bu4NClO4
(4.70 g) was electrolyzed (1.6–2.2 V vs SCE, 30 mA, 4.0 F/mol).
The reaction mixture was evaporated, and the residue was chro-
matographed on a silica-gel column (hexane–EtOAc 1/1) to give
oily 75 (15.8 mg, 36%) and unreacted 5 (2.9 mg, 6%).
ꢂ
Synthesis of 2-Bromo-4-(3-hydroxypropyl)-6-(trifluoro-
methyl)phenol (15c): To a solution of 15b (133 mg, 0.6 mmol)
in CHCl3 (4 mL) was added a solution of Pyr HBr3 (193 mg, 0.6
ꢁ
mmol) at room temperature; the mixture was stirred for 1.5 h. The
reaction mixture was diluted with CHCl3, and washed with H2O,
sat. aq. Na2S2O3, and brine. The organic layer was dried
(Na2SO4), and evaporated. The crude oil was chromatographed
on a silica-gel column (hexane–EtOAc 7/2) to afford 15c (174
mg, 96%) as an oil: IR (NaCl) 3336, 2944, 1617, 1483, 1319,
1
1132 cmꢃ1; H NMR ꢀ 1.86 (2H, tt, J ¼ 6:6, 7.8 Hz), 2.68 (2H,
t, J ¼ 7:8 Hz), 3.68 (2H, t, J ¼ 6:6 Hz), 7.34 (1H, s), 7.50 (1H,
s); 13C NMR ꢀ 30.8, 33.9, 61.7, 111.7, 117.7 (q, J ¼ 31:4 Hz),
122.9 (q, J ¼ 271:5 Hz), 126.4 (q, J ¼ 5 Hz), 135.0, 135.2,
148.2 (q, J ¼ 1:6 Hz); HRMS found m=z 279.9717, calcd for
C10H8F379BrO: M ꢃ H2O, 279.9711.
Procedure of PIFA Oxidation: To a solution of 15b (51.2
mg, 0.23 mmol)ꢂin MeCN (5 mL) was added PIFA (161 mg,
0.38 mmol) at 0 C; the mixture was stirred at room temperature
for 1 h. The reaction mixture was diluted with EtOAc, washed
with H2O and brine, dried (Na2SO4), and then evaporated. The
residue was chromatographed on a silica-gel column (hexane–
EtOAc 4/1) to afford 20b (23.6 mg, 47%): IR (NaCl) 2983,
Synthesis of 2-Fluoro-4-(3-hydroxypropyl)phenol (15d): To
a solution of 18 (1.96 g, 6.6 mmol) in DMF (15 mL) were added
Et3N (15 mL), methyl acrylate (2.98 mL, 33 mmol), and
Pd(ꢂdppf)2Cl2 (269 mg, 0.33 mmol); the mixture was stirred at
90 C for 12 h. After evaporation, the remaining mixture was di-
luted with H2O (100 mL), and washed with EtOAc–hexane (1/1).
The combined organic layer was washed with brine, dried
(Na2SO4), and evaporated. The residue was chromatographed on
a silica-gel column (hexane–EtOAc 10/1 to 4/1) to afford an ester
(1.55 g, 82%): mp 91.5–93 ꢂC (needles, EtOAc–hexane): IR
2881, 1687, 1651, 1398, 1298, 1140, 1034 cmꢃ1 1H NMR ꢀ
;
2.15 (2H, complex), 2.22 (2H, complex), 4.13 (2H, complex),
6.18 (1H, d, J ¼ 10 Hz), 6.86 (1H, dd, J ¼ 3:2, 10 Hz), 7.27
(1H, broad s); 13C NMR ꢀ 26.8, 37.0, 69.8, 77.0, 121.2 (q, J ¼
267:0 Hz), 126.9, 127.1 (q, J ¼ 29:6 Hz), 149.3, 150.0 (q, J ¼
4:9 Hz), 179.7; HRMS found m=z 218.0562, calcd for C10H9F3O2:
M, 218.0554.
(KBr) 2952, 1706, 1637, 1152, 1273, 1173 cmꢃ1
;
1H NMR ꢀ
9-Chloro-7-methyl-1-oxaspiro[4.5]deca-6,9-dien-8-one (20a):
1
3.79 (3H, s), 5.17 (2H, s), 6.29 (1H, d, J ¼ 16:1 Hz), 6.98 (1H,
t, J ¼ 8:8 Hz), 7.19 (1H, broad d, J ¼ 8:8 Hz), 7.29 (1H, dd,
J ¼ 12:2, 2.2 Hz), 7.32–7.45 (5H, complex), 7.58 (1H, d, J ¼
16:1 Hz); 13C NMR ꢀ; HRMS found m=z 286.1023, calcd for
C17H15FO3: M, 286.1005.
A solution of the benzyl ether (0.93 g, 3.3 mmol) in EtOAc (40
mL) in the presence of a catalytic amount of 10% Pd/C was stir-
red for 2 h under a hydrogen atmosphere. After filtration, the fil-
trate was evaporated, and the residue was chromatographed on a
silica-gel column (hexane–EtOAc 9/1) to afford a phenol (0.63
IR (NaCl) 2954, 1672, 1612, 1328, 1032 cmꢃ1; H NMR ꢀ 1.93
(3H, d, J ¼ 1:5 Hz), 2.07–2.19 (4H, complex), 4.07 (2H, com-
plex), 6.59 (1H, dd, J ¼ 1:5, 2.9 Hz), 6.96 (1H, d, J ¼ 2:9 Hz);
13C NMR ꢀ 16.1, 26.8, 36.8, 69.2, 78.8, 131.3, 133.1, 145.1,
145.2, 179.2; HRMS found m=z 200.0399, calcd for
C10H1137ClO2: M, 200.0417. Found: C, 60.41; H, 5.57%. Calcd
for C10H11ClO2: C, 60.46; H, 5.58%.
9-Bromo-7-(trifluoromethyl)-1-oxaspiro[4.5]deca-6,9-dien-8-
one (20c): IR (NaCl) 2881, 1691, 1381, 1290, 1146, 1022 cmꢃ1
;
1H NMR ꢀ 2.23 (4H, complex), 4.14 (2H, complex), 7.28 (2H, s);

2262 Bull. Chem. Soc. Jpn., 77, No. 12 (2004)
Chemistry and Activity of Chroman Derivatives
13C NMR ꢀ 26.8, 36.9, 70.0, 78.8, 120.8 (q, J ¼ 273 Hz), 122.5 (q,
J ¼ 2:4 Hz), 126.2 (q, J ¼ 30:6 Hz), 149.5, 150.2 (q, J ¼ 4:1 Hz),
173.1; HRMS found m=z 295.9649, calcd for C10H879BrF3O2: M,
295.9659.
7-Bromo-5-(trifluoromethyl)chroman-6-ol (22c): mp 89–90
ꢂC (needles, hexane–Et2O); IR (KBr) 3456, 2941, 1487, 1433,
1117, 1039 cmꢃ1; 1H NMR ꢀ 2.05 (2H, complex), 2.76 (2H, com-
plex), 4.12 (2H, complex), 7.03 (1H, s); 13C NMR ꢀ 22.0, 26.6,
65.9, 114.4 (q, J ¼ 4:9 Hz), 115.7 (q, J ¼ 32:2 Hz), 122.8 (q, J ¼
271:7 Hz), 126.6, 126.6, 143.4 (q, J ¼ 1:6 Hz), 148.8; HRMS
found m=z 295.9676, calcd for C10H8F379BrO2: M, 295.9660.
7-Fluorochroman-6-ol (22d): IR (NaCl) 3381, 2937, 1610,
7-Fluoro-1-oxaspiro[4.5]deca-6,9-dien-8-one (20d):
;
IR
(NaCl) 2981, 2879, 1685, 1365, 1161, 1034 cmꢃ1 1H NMR ꢀ
2.12–2.21 (4H, complex), 4.09 (2H, complex), 6.16 (1H, dd,
J ¼ 7:3, 9.8 Hz), 6.36 (1H, dd, J ¼ 3, 12.7 Hz), 6.83 (1H, dd,
J ¼ 3, 9.8 Hz); 13C NMR ꢀ 26.7, 37.1 (d, J ¼ 2:5 Hz), 69.3,
79.5 (d, J ¼ 8:3 Hz), 125.0 (d, J ¼ 0:8 Hz), 125.8 (d, J ¼ 2:7
Hz), 150.5 (d, J ¼ 2:5 Hz), 152.1 (d, J ¼ 264 Hz), 178.2 (d, J ¼
19:9 Hz); HRMS found m=z 168.0596, calcd for C9H9FO2: M,
168.0586.
1508, 1288, 1153 cmꢃ1 1H NMR ꢀ 1.96 (2H, complex), 2.69
;
(2H, complex), 4.11 (2H, complex), 6.55 (1H, d, J ¼ 11:7 Hz),
6.66 (1H, d, J ¼ 9:8 Hz); 13C NMR ꢀ 22.2, 24.4, 66.3, 103.9 (d,
J ¼ 21:5 Hz), 117.0 (d, J ¼ 3:3 Hz), 118.0 (d, J ¼ 4:0 Hz),
136.6, 148.1 (d, J ¼ 23:1 Hz), 149.3 (d, J ¼ 248 Hz); HRMS
found m=z 168.0579, calcd for C9H9FO2: M, 168.0586.
5-Chlorochroman-6-ol (21e): IR (NaCl) 3438, 2927, 1483,
1176, 1066 cmꢃ1; 1H NMR ꢀ 2.02 (2H, complex), 2.76 (2H, com-
plex), 4.09 (2H, complex), 5.16 (1H, broad s), 6.67 (1H, d, J ¼
8:9 Hz), 6.80 (1H, d, J ¼ 8:9 Hz); HRMS found m=z 184.0277,
calcd for C9H935ClO2: M, 184.0290.
7-Chlorochroman-6-ol (22e): IR (NaCl) 3423, 2935, 1489,
1180, 1061 cmꢃ1; 1H NMR ꢀ 1.97 (2H, complex), 2.72 (2H, com-
plex), 4.12 (2H, complex), 5.07 (1H, broad s), 6.69 (1H, s), 6.77
(1H, s); 13C NMR ꢀ 22.1, 24.6, 66.3, 116.0, 116.3, 117.6, 122.4,
144.5, 148.6; HRMS found m=z 184.0301, calcd for C9H935ClO2
184.0290.
7-Chloro-1-oxaspiro[4.5]deca-6,9-dien-8-one (20e):
;
IR
(NaCl) 2956, 1676, 1604, 1340, 1032 cmꢃ1 1H NMR ꢀ 2.08–
2.23 (4H, complex), 4.10 (2H, complex), 6.24 (1H, d, J ¼ 10
Hz), 6.83 (1H, dd, J ¼ 2:8, 10 Hz), 6.99 (1H, d, J ¼ 2:8 Hz);
13C NMR ꢀ 26.8, 37.0, 69.5, 79.3, 126.1, 131.3, 145.4, 150.0,
178.4; HRMS found m=z 184.0258, calcd for C9H935ClO2: M,
184.0290.
Procedure of the Ring Expansion: To a solution of 20d
(23.3 mg, 0.139 mmol) in CH2Cl2 (1.4 mL) was added BF3 Et2O
ꢁ
(52.8 mL, 0.42 mmol) at 0 ꢂC; the mixture was stirred at room
temperature until the starting material was disappeared. The reac-
tion was diluted with EtOAc (30 mL), washed with H2O and brine
(30 mL), dried (Na2SO4), and evaporated. The residue was chro-
matographed on a silica-gel column (hexane–EtOAc 8/1) to af-
ford 22d (14.7 mg, 63%).
Bioassay. Effects for Coleoptile and Root Growth of Oat
(Avena sativa L.): Ten seeds of oat were put on a dish, in which
1 mL of a test solution was added. After incubation at 25 ꢂC for 3
days in the dark, the lengths of coleoptiles and roots of the seed-
lings were measured. Oat incubated without test samples during
the same period was used as control.
A Mixture of 5-Chloro-7-methylchroman-6-ol (21a) and 5-
Chloro-7-methylchroman-6-ol (22a): IR (NaCl) 3456, 2952,
;
1483, 1415, 1157, 1066 cmꢃ1 1H NMR ꢀ 2.00 (3H, complex),
2.15 (1.5H, s), 2.22 (3H, s), 2.62 (1H, m), 2.71 (2H, complex),
4.07 (3H, complex), 5.20 (0.5H, broad s), 5.23 (1H, broad s),
6.55 (1H, s), 6.68 (0.5H, s); 13C NMR ꢀ 11.9, 16.3, 22.2, 22.4,
22.9, 23.3, 65.8, 65.8, 113.6, 117.1, 117.6, 119.2, 123.6, 143.3,
148.4; HRMS found m=z 198.0470, calcd for C10H1135ClO2: M,
198.0447. Found: C, 60.84; H, 5.76%. Calcd for C10H11ClO2:
C, 60.46; H, 5.58%.
Effects for Hypocotyl and Root Growth of Cress (Lepidium
sativum L.): Ten seeds of cress in the presence of a 0.5 mL solu-
tion of a test sample were incubated at 23 C in the dark. After 2
days, the length of the roots was measured, and hypocotyls were
measured after being incubated one more day.
ꢂ
This work was supported by a Grant-in-Aid for the 21st
Century COE program ‘‘KEIO Life Conjugate Chemistry’’,
as well as Scientific Research C from the Ministry of Educa-
tion, Culture, Sports, Science and Technology.
7-(Trifluoromethyl)chroman-6-ol (21b): mp 82–83 ꢂC (nee-
dles, hexane); IR (KBr) 3377, 2974, 1618, 1458, 1375, 1275,
1124, 1072 cmꢃ1; 1H NMR ꢀ 1.98 (2H, complex), 2.88 (2H, com-
plex), 4.12 (2H, complex), 6.74 (1H, d, J ¼ 8:8 Hz), 6.88 (1H, d,
J ¼ 8:8 Hz); 13C NMR ꢀ 21.9, 22.8 (q, J ¼ 4:1 Hz), 65.6, 113.4
(q, J ¼ 27:3 Hz), 117.6, 120.8, 122.3, 125.6 (q, J ¼ 273:1 Hz),
147.9 (q, J ¼ 2:5 Hz), 148.9; HRMS found m=z 218.0571, calcd
for C10H9F3O2: M, 218.0554.
References
1 Recent review. See: S. Yamamura and S. Nishiyama, Syn-
lett, 2002, 533.
5-(Trifluoromethyl)chroman-6-ol (22b):
(needles, hexane); IR (KBr) 3394, 2924, 1639, 1434, 1329,
1277, 1115, 1030 cmꢃ1 1H NMR ꢀ 1.99 (2H, complex), 2.75
mp 96.5–97 ꢂC
2
a) K. Mori, M. Takahashi, S. Yamamura, and S. Nishiyama,
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(2H, complex), 4.15 (2H, complex), 6.64 (1H, s), 6.94 (1H, s);
13C NMR ꢀ 22.0, 24.9, 66.4, 114.5 (q, J ¼ 4:9 Hz), 115.4 (q, J ¼
29:8 Hz), 118.4, 123.8 (q, J ¼ 270:8 Hz), 127.8, 146.1 (q, J ¼ 2:5
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218.0554.
3
F. A. Macias, R. M. Varela, A. Torres, and J. M. G.
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100 ꢂC (needles, hexane–Et2O); IR (NaCl) 3487, 1460, 1107,
5
F. Doi, T. Ohara, T. Ogamino, T. Sugai, K. Higashinakasu,
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1
1070 cmꢃ1; H NMR ꢀ 1.97 (2H, complex), 2.89 (2H, complex),
4.11 (2H, complex), 7.15 (1H, s); 13C NMR ꢀ 21.7 (q, J ¼ 1:6
Hz), 23.0 (q, J ¼ 4:1 Hz), 65.7, 110.3, 115.4 (q, J ¼ 29 Hz),
122.1 (q, J ¼ 1:7 Hz), 123.9, 124.3 (q, J ¼ 275 Hz), 144.5 (q, J ¼
1:6 Hz), 148.9; HRMS found m=z 295.9666, calcd for
C10H8F379BrO2: M, 295.9660.
6
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