A facile preparation, spectroscopic and chemical properties, crystal structures, and electrochemical behavior of monocarbenium ion compounds stabilized by 3-guaiazulenyl and dihydroxyphenyl (or hydroxymethoxyphenyl) groups

Article abstract of DOI:10.1016/j.tet.2011.09.148

Reaction of guaiazulene (8) with 2,3-dihydroxybenzaldehyde (9) in methanol in the presence of hexafluorophosphoric acid (i.e., 65% aqueous solution) at 25 °C for 2 h gives (3-guaiazulenyl)(2,3-dihydroxyphenyl)methylium hexafluorophosphate (13) in 86% yiel

Full text of DOI:10.1016/j.tet.2011.09.148

Tetrahedron 67 (2011) 9719e9728
Contents lists available at SciVerse ScienceDirect
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journal homepage: www.elsevier.com/locate/tet
A facile preparation, spectroscopic and chemical properties, crystal structures,
and electrochemical behavior of monocarbenium ion compounds stabilized
by 3-guaiazulenyl and dihydroxyphenyl (or hydroxymethoxyphenyl) groups
,
a
a
b
Shin-ichi Takekuma a , Ippei Miyamoto , Akio Hamasaki , Toshie Minematsu
*
a Department of Applied Chemistry, Faculty of Science and Engineering, Kinki University, 3-4-1 Kowakae, Higashi-Osaka-shi, Osaka 577-8502, Japan
b School of Pharmaceutical Sciences, Kinki University, 3-4-1 Kowakae, Higashi-Osaka-shi, Osaka 577-8502, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 July 2011
Received in revised form 26 September 2011
Accepted 29 September 2011
Available online 8 October 2011
Reaction of guaiazulene (8) with 2,3-dihydroxybenzaldehyde (9) in methanol in the presence of hexa-
fluorophosphoric acid (i.e., 65% aqueous solution) at 25 ꢀC for
2 h gives (3-guaiazulenyl)(2,3-
dihydroxyphenyl)methylium hexafluorophosphate (13) in 86% yield. Similarly, reaction of 8 with 2-
hydroxy-3-methoxybenzaldehyde (10) [or 3,4-dihydroxybenzaldehyde (11) or 4-hydroxy-3-
methoxybenzaldehyde (12)] under the same reaction conditions as for 9 affords the corresponding
monocarbenium ion compound 14 (63% yield) [or 15 (43% yield) or 16 (77% yield)], respectively, each
product of which is stabilized by 3-guaiazulenyl and dihydroxyphenyl (or hydroxymethoxyphenyl)
groups. A facile preparation and crystal structures as well as spectroscopic, chemical, and electrochemical
properties of 13e16, possessing two interesting resonance structures, respectively, i.e., a protonated o-
(or p-) benzoquinonemethide form and a 3-guaiazulenylium ion form, in a solution of acetonitrile and
further, in a single crystal, are reported.
Keywords:
Dihydroxybenzaldehydes
Electrochemical behavior
Facile preparation
Guaiazulene
3-Guaiazulenylium ion
Hexafluorophosphoric acid
Intramolecular hydrogen bond
Hydroxymethoxybenzaldehydes
Monocarbenium ions
NaBH4-reduction
Ó 2011 Elsevier Ltd. All rights reserved.
Protonated benzoquinonemethides
Spectroscopic properties
X-ray crystal structures
1. Introduction
crystallographic analyses, of delocalized methylium ion compounds
stabilized by azulen-1-yl (or alkyl-substituted azulen-1-yl) and 4-
In 1996 Atwood et al. reported a crystal and molecular structure
of the [H3O$18-crown-6]2[ReCl6] 1 isolated from a liquid clathrate
medium as the first example for the crystal structure of the oxonium
ion H3Oþ (see Chart 1),1 while the hydrogen atoms of 1 were not
refined and further, the related studies have been documented.2ꢁ8
The hydrogen atoms of the oxonium ion H3Oþ were refined in
2007, and the corresponding three OeH bond lengths tended to be
hydroxyphenyl (or 4-methoxyphenyl) groups.11ꢁ13 On the other
hand, we have been working on basic and systematic investigations
using
a
naturally occurring guaiazulene14 (¼7-isopropyl-1,4-
dimethylazulene) (8), whose compound has been widely used
clinically as an anti-inflammatory and anti-ulcer agent, and have
reported a facile preparation and crystal structures as well as
spectroscopic, chemical, and electrochemical properties of extended
5
ꢀ
0.86 A, the bond length of which was characteristically shorter in
p
-electron systems possessing a 3-guaiazulenyl (¼5-isopropyl-3,8-
dimethylazulen-1-yl) group.15ꢁ40 In relation to the study on the
molecular structure of 2,10 in 2005 we found that the reaction of 8
with 2- (or 4-) hydroxybenzaldehyde in methanol in the presence of
hexafluorophosphoric acid at 25 ꢀC for 2 h gave the corresponding
monocarbenium ion compound 3 (or 6),25 possessing two in-
teresting resonance structures, respectively, i.e., a protonated o- (or
p-) benzoquinonemethide form and a 3-guaiazulenylium ion form
in acetonitrile (see Chart 2), while each X-ray crystallographic
analysis of 3 (and 6) could not be achieved because of difficulty in
obtaining a single crystal suitable for that purpose. Furthermore, in
ꢀ
comparison with that of water molecule (0.96 A). Along with those
studies, in 1997 Yamaguchi, Tamura, and Maeda reported a unique
crystal structure of the phenolsulfonphthalein9 2, with a zwitter-
ionic form, whose molecular structure possesses an interesting
protonated p-benzoquinonemethide form (see Chart 1);10 however,
the hydrogen atoms of 2 were not refined. Besides the above, Ito
et al. reported synthesis and properties, with the exception of X-ray
* Corresponding author. Tel.: þ81 6 6721 2332x5222; fax: þ81 6 6727 2024;
e-mail address: takekuma@apch.kindai.ac.jp (S. Takekuma).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.148

9720
S.-i. Takekuma et al. / Tetrahedron 67 (2011) 9719e9728
2007 we reported a comparative study on the crystal structures of
(3-guaiazulenyl)(2-methoxyphenyl)methylium tetrafluoroborate41
(4BF4), 5, and 7 (see Chart 2), whose hydrogen atoms could not be
refined.32 Interestingly, the structural parameters for the X-ray
crystallographic analyses of 4BF4 and 7 suggested the crystal
structures with similar resonance structures to 3 and 6 in acetoni-
trile. During the course of our basic and systematic investigations on
the above,15ꢁ41 we have quite recently discovered the unique
monocarbenium ion compounds 14 and 15 (see Chart 2), apparently
possessing two representative resonance structures, respectively,
i.e., the protonated o- (and p-) benzoquinonemethide forms 14a
(and 15a) and the 3-guaiazulenylium ion forms 14b (and 15b) in
a solution of acetonitrile and further, in a single crystal (see Chart 3).
We now wish to report the detailed title studies: namely, a facile
preparation and crystal structures as well as spectroscopic, chem-
ical, and electrochemical properties of our systematic mono-
carbenium ion compounds 13e16 stabilized by 3-guaiazulenyl and
dihydroxyphenyl (or hydroxymethoxyphenyl) groups with a view to
comparative study (see Chart 2).
(PF6ꢁ) of 13 coincided with those of 3 (nmax 845 and 559 cmꢁ1).25 The
formula C22H23O2 for the monocarbenium ion structure [MꢁPF6]þ
was determined by exact FABMS spectrum. An elemental analysis
confirmed the formula C22H23O4F6P (i.e., C22H23O2þPF6þO2). The 1H
NMR spectrum for 13 showed signals based on
a 2,3-
dihydroxyphenyl group with a similar resonance structure to the
protonated quinonemethide form 14a (see Chart 3) and further,
revealed signals based on a 3-guaiazulenylmethylium ion unit with
a similar resonance structure to the 3-guaiazulenylium ion form 14b
(see Chart 3), the signals of which were carefully assigned using DQF
COSY and computer-assisted simulation based on first-order anal-
ysis (see Tables 2 and 3 and Section 4.1.1). The 13C NMR spectrum
exhibited 21 carbon signals assigned by HSQC and HMBC (see Tables
4 and 5 and Section 4.1.1), the assignments of which support a (3-
guaiazulenyl)(2,3-dihydroxyphenyl)methylium
ion
structure.
Thus, the elemental analysis and the total spectroscopic analyses for
13 led to the target monocarbenium ion structure (3-guaiazule-
nyl)(2,3-dihydroxyphenyl)methylium hexafluorophosphate.
Table 2
The 1H NMR chemical shifts (
d) for the dihydroxyphenyl (and hydroxymethox-
yphenyl) groups of 13e18
2. Results and discussion
Compound H-2 H-3 H-4 H-5 H-6 CH3O-3 HO-2 HO-3 HO-4
2.1. Preparation and spectroscopic properties of 13e16
a
a
13
14
15
16
17
18
d
d
d
d
d
d
d
7.07 6.93 7.22
7.16 7.03 7.30 3.93
d
d
d
7.58
d
d
d
The target monocarbenium ion compounds 13e16 were pre-
pared according to the procedures shown in Scheme 1, Table 1, and
Sections 4.1.1e4.1.4. The structures of the products 13e16 were
established on the basis of elemental analysis and spectroscopic
data [UVevis, IR, exact FABMS, and 1H and 13C NMR including 2D
NMR (i.e., DQF COSY, HSQC, and HMBC)].
7.41
7.45
d
d
d
7.04 7.38
7.01 7.50 3.98
d
7.25
d
7.87
7.69
d
d
6.78 6.63 6.13 3.85
6.66 6.34 3.73
6.57
d
d
6.72
d
d
6.28
a
The OH signal was included in a signal of slightly existing water molecule in
CD3CN.
Table 3
The 1H NMR chemical shifts (
d) for the 3-guaiazulenylmethylium ion units of 13e16
and the 3-guaiazulenylmethyl groups of 17 and 18
Compound HCþ Me-10 H-20 Me-40 H-50 H-60 (CH3)2CH-70 (CH3)2CH-70 H-80
-a
13
14
15
16
17
18
9.00 2.50 7.99 3.33 8.48 8.38 3.48
9.02 2.50 8.00 3.33 8.47 8.38 3.48
8.65 2.53 8.09 3.32 8.42 8.35 3.46
8.72 2.54 8.12 3.34 8.42 8.35 3.46
4.49a 2.56 7.32 2.77 6.80 7.28 3.03
4.48a 2.56 7.37 2.82 6.80 7.28 3.02
1.45
1.45
1.46
1.44
1.31
1.30
8.57
8.57
8.56
8.57
8.09
8.09
a
CH2-30.
Scheme 1. The reactions of
8 with 9e12 in methanol in the presence of hexa-
fluorophosphoric acid (i.e., 65% aqueous solution) at 25 ꢀC for 2 h, yielding the cor-
responding monocarbenium ion compounds 13e16.
Table 4
The 13C NMR chemical shifts (
yphenyl) groups of 13e18
d) for the dihydroxyphenyl (and hydroxymethox-
Table 1
The isolated yields (%) of the products 13e16 obtained by the reactions of 8 with
9e12 in methanol in the presence of hexafluorophosphoric acid (i.e., 65% aqueous
solution) at 25 ꢀC for 2 h
Compound
C-1
C-2
C-3
C-4
C-5
C-6
CH3O-3
13
14
15
16
17
18
145.4
149.2
129.2
129.0
130.3
136.2
148.2
148.6
120.1
117.1
143.9
112.9
124.2
123.3
146.6
149.2
147.6
148.1
120.3
116.3
151.8
153.2
109.9
144.9
121.8
121.6
117.4
117.2
120.1
115.4
125.5
125.5
130.3
130.9
122.8
121.7
d
57.0
d
Entry
Substituent
Temp/ꢀC
Time/h
Product
Yield/%
57.0
56.7
56.6
R1
R2
R3
1
2
3
4
OH
OH
H
OH
OCH3
OH
H
H
OH
OH
25
25
25
25
2
2
2
2
13
14
15
16
86
63
43
77
Although a single crystal of compound 13 could not be obtained
under numerous recrystallization conditions, that of compound 14
could be obtained as dark-red needles from a mixed recrystallization
solvent of acetonitrile and diethyl ether (1:5, vol/vol) (see Section
4.1.2). The UVevis spectrum showed that the longest absorption
wavelength of 14 (lmax 486 nm) (see Fig. 1) coincided with those of 3
H
OCH3
Compound 13 was obtained as a dark-red powder (see Section
4.1.1). The IR spectrum showed that although a specific band (nmax
3452 cmꢁ1) from two hydroxy groups of 13 revealed a low wave-
number shift in comparison with that of 3 (nmax 3483 cmꢁ1),25 two
specific bands (nmax 841 and 559 cmꢁ1) based on the counter anion
(
lmax 489 nm)25 and 4 (lmax 487 nm);32 however, the molar extinc-
tioncoefficient(log
comparisonwith thoseof3 (log
3
¼4.12)ofwhichrevealed ahypochromiceffectin
3
¼4.50)25 and 4(log
3
¼4.44).32 TheIR

S.-i. Takekuma et al. / Tetrahedron 67 (2011) 9719e9728
9721
Table 5
The selected 13C NMR chemical shifts (
d
) for the 3-guaiazulenylmethylium ion units of 13e16 and the 3-guaiazulenylmethyl groups of 17 and 18
Compound
HCþ
-a
C-10
C-20
C-30
C-3a0
C-40
C-50
C-60
C-70
C-80
C-8a0
13
14
15
16
17
18
146.0
145.6
151.8
151.8
31.4a
37.1a
145.7
145.4
146.6
144.6
125.0
125.1
142.1
141.9
141.8
141.8
141.7
141.9
139.4
139.4
137.5
137.5
126.4
127.3
153.6
153.6
153.3
153.3
133.9
133.7
157.6
157.5
157.1
157.1
146.4
146.4
150.3
150.3
149.0
149.0
126.8
127.0
144.8
144.7
144.3
144.3
135.7
135.7
171.0
171.0
169.2
169.2
139.8
139.9
139.8
139.8
139.6
139.6
134.2
134.3
161.2
161.2
159.6
159.6
138.7
138.8
a
CH2-30.
based on a 3,4-dihydroxyphenyl group with the resonance structure
15a (see Chart 3) and further, revealed signals based on a 3-
guaiazulenylmethylium ion unit with the resonance structure 15b
(see Chart 3), the signals of which were carefullyassigned using similar
analyses to those of 13 (see Tables 2 and 3 and Section 4.1.3). The 13
C
NMR spectrum exhibited 21 carbon signals assigned using similar
analyses to those of 13 (see Tables 4 and 5 and Section 4.1.3), the
assignments
of
which
support
a
(3-guaiazulenyl)(3,4-
dihydroxyphenyl)methylium ion structure. Thus, the elemental
analysis and the total spectroscopic analyses for 15 led to the target
monocarbenium ion structure (3-guaiazulenyl)(3,4-dihydroxy-
phenyl)methylium hexafluorophosphate.
Compound 16 was obtained as dark-red blocks under the same
recrystallization conditions as for 15, while a single crystal suitable
for X-ray crystallographic analysis of 16 could not be obtained (see
Section 4.1.4). The UVevis spectrum showed that the longest ab-
sorption wavelength and the molar extinction coefficient of 16
Fig. 1. The UVevis spectra of 14 and 15 in CH3CN. Concentrations, 14: 0.13 g Lꢁ1
(242
mol Lꢁ1), 15: 0.14 g Lꢁ1 (290 mol Lꢁ1). Length of cell: 0.1 cm each. Each log
value is given in parenthesis.
m
m
3
spectrum showed that although a specific band (nmax 3452 cmꢁ1
)
(
lmax 527 nm, log
3
¼4.59) coincided with those of 15. The IR
from a hydroxy group of 14 revealed a low wavenumber shift in
comparison with that of 3,25 the wavenumber of which coincided
with that of 13, and further, that two specific bands (nmax 841 and
559 cmꢁ1) based on the counter anion (PFꢁ6 ) of 14 coincided with
those of 3,25 4 (nmax 841 and 559 cmꢁ1),32 and 13. The formula
spectrum showed that although a specific band (nmax 3468 cmꢁ1
)
from a hydroxy group of 16 revealed a high wavenumber shift in
comparison with those of 15, two specific bands (nmax 841 and
559 cmꢁ1) based on the counter anion (PFꢁ6 ) of 16 coincided with
those of 15. The formula C23H25O2 for the monocarbenium ion
structure [MꢁPF6]þ was determined by exact FABMS spectrum. An
elemental analysis confirmed the formula C25H28O4NF6P (i.e.,
C
23H25O2 for the monocarbenium ion structure [MꢁPF6]þ was de-
termined byexact FABMS spectrum. An elementalanalysis confirmed
the formula C25H28O3NF6P (i.e., C23H25O2þPF6þCH3CNþ1/2O2). The
1H NMR spectrum for 14 showed signals based on a 2-hydroxy-3-
methoxyphenyl group with the resonance structure 14a (see Chart
3) and further, revealed signals based on a 3-guaiazulenylmethy-
lium ion unit with the resonance structure 14b (see Chart 3), the
signals of which were carefully assigned using similar analyses to
those of 13 (see Tables 2 and 3 and Section 4.1.2). The 13C NMR
spectrum exhibited 22 carbon signals assigned using similar analyses
tothose of13 (see Tables 4 and 5 and Section 4.1.2), theassignmentsof
C
23H25O2þPF6þCH3CNþO2). The 1H NMR spectrum for 16 showed
signals based on a 4-hydroxy-3-methoxyphenyl group with a sim-
ilar resonance structure to the protonated quinonemethide form
15a (see Chart 3) and further, revealed signals based on a 3-
guaiazulenylmethylium ion unit with a similar resonance struc-
ture to the 3-guaiazulenylium ion form 15b (see Chart 3), the sig-
nals of which were carefully assigned using similar analyses to
those of 13 (see Tables 2 and 3 and Section 4.1.4). The 13C NMR
spectrum exhibited 22 carbon signals assigned using similar anal-
yses to those of 13 (see Tables 4 and 5 and Section 4.1.4), the as-
which support
a (3-guaiazulenyl)(2-hydroxy-3-methoxyphenyl)
methylium ion structure. Thus, the elemental analysis and the total
spectroscopic analyses for 14 led to the target monocarbenium ion
structure (3-guaiazulenyl)(2-hydroxy-3-methoxyphenyl)methylium
hexafluorophosphate.
A single crystal of compound 15 was obtained as dark-red blocks
under the same recrystallization conditions as for 14 (see Section
4.1.3). The UVevis spectrum showed that the longest absorption
signments of which support
a (3-guaiazulenyl)(4-hydroxy-3-
methoxyphenyl)methylium ion structure. Thus, the elemental
analysis and the total spectroscopic analyses for 16 led to the target
monocarbenium ion structure (3-guaiazulenyl)(4-hydroxy-3-
methoxyphenyl)methylium hexafluorophosphate.
The HCþ-
a
proton NMR signals of 13 and 14 (
showed larger down-field shifts in comparison with those of 15 and
16 ( 8.65 and 8.72), suggesting the formation of the C eH/OeC2
hydrogen bond. Similarly, the HCþ-
proton NMR signals of the pre-
d 9.00 and 9.02)
wavelength of 15 (lmax 530 nm, log
3
¼4.54) revealed a bathochromic
d
a
shift and a hyperchromic effect in comparison with that of 14 (see
Fig. 1) and further, that the wavelength of which revealed a bath-
ochromic shift and a hypochromic effect in comparison with that of 6
a
viously reported compounds 325 and 432
(d 9.01 and 9.04) revealed
larger down-field shifts in comparison with those of 625 and 732
8.72 and 8.74), owing to the same influence as for 13 and 14.
(d
(
lmax 510 nm, log
3
¼4.67).25 The IR spectrum showed that although
two specific bands (nmax 3444 and 3274 cmꢁ1) from two hydroxy
groups of 15 revealed low wavenumber shifts in comparisonwith that
of 6 (nmax 3476 cmꢁ1),25 two specific bands (nmax 844 and 559 cmꢁ1
)
based on the counter anion (PFꢁ6 ) of 15 coincided with those of 6 (nmax
837 and 556 cmꢁ1).25 The formula C22H23O2 for the monocarbenium
ion structure [MꢁPF6]þ was determined byexact FABMS spectrum. An
2.2. Hydride-reductions of 14 and 16 with NaBH4
Although the hydride-reductions of the (3-guaiazulenyl)-
(dihydroxyphenyl)methylium hexafluorophosphates 13 and 15
with NaBH4 in a mixed solvent of ethanol and acetonitrile at 25 ꢀC
elemental analysis confirmed the formula
C22H23O3F6P (i.e.,
C
22H23O2þPF6þ1/2O2). The 1H NMR spectrum for 15 showed signals

9722
S.-i. Takekuma et al. / Tetrahedron 67 (2011) 9719e9728
for 1 h gave several products simultaneously, the hydride-
reductions of the 1-hydroxy-2-methoxybenzene derivatives 14
and 16 with NaBH4 under the same reaction conditions as for 13
and 15 afforded 17 and 18 quantitatively (94% yield each) (see
Scheme 2 and Table 6). Thus, a hydride-ion attached to each HCþ-
with those of 18 are shown inTables 2ꢁ5, leading to the formation of
16 with two representative resonance structures of the protonated
p-benzoquinonemethide form and the 3-guaiazulenylium ion form.
From the detailed comparative NMR studies of 16 with 15 (see Tables
2ꢁ5), it can be inferred that 16 possesses similar resonance struc-
tures to 15 (see Chart 3) in acetonitrile-d3.
a
position of 14 and 16 selectively.
2.3. X-ray crystal structure of 14 compared with that of the
related carbenium ion compound (3-guaiazulenyl)(2-
methoxyphenyl)methylium tetrafluoroborate (4BF4)
Although it was very difficult to obtain a single crystal of 13
suitable for X-ray crystallographic analysis, the recrystallization of
14 from a mixed solvent of acetonitrile and diethyl ether (1:5, vol/
vol) provided a stable single crystal suitable for that purpose. Thus,
the crystal structure of 14 could be determined by means of X-ray
diffraction, producing accurate structural parameters (see Section
4.1.7). Non-hydrogen atoms were refined anisotropically and fur-
ther, hydrogen atoms could be refined isotropically. The ORTEP
drawing of 14 with a numbering scheme, indicating the structure
illustrated in Chart 2, is shown in Fig. 2a along with the selected
bond lengths (see Table 7). The results are as follows. The plane of
the benzene ring of 14 twisted by 5.3ꢀ from that of the 3-
guaiazulenylmethylium ion unit, owing to the influence of steric
hindrance and steric repulsion between the hydrogen atoms of the
C6 and C20 positions (see the space-filling structure of 14 shown in
Fig. 2c), the torsion angle of which was smaller than that of 4BF4
(35.4ꢀ).32 Similar to 4BF4, the 3-guaiazulenylmethylium ion unit of
14 clearly underwent bond alternation between single and double
bonds as shown in Table 7. The 2-hydroxy-3-methoxybenzene ring
of 14 also clearly underwent bond alternation between single and
double bonds as shown in Table 7. The average CeC bond length for
the seven-membered ring of the 3-guaiazulenyl group of 14
Scheme 2. The hydride-reductions of 14 (and 16) with NaBH4 in a mixed solvent of
ethanol and acetonitrile at 25 ꢀC for 1 h, yielding 17 (and 18) quantitatively.
Table 6
The isolated yields (%) of the products 17 (and 18) obtained by the hydride-
reductions of 14 (and 16) with NaBH4 in a mixed solvent of ethanol and acetoni-
trile at 25 ꢀC for 1 h
Entry
Substituent
Temp/ꢀC
Time/h
Product
Yield/%
R1
R2
R3
1
2
OH
H
OCH3
OCH3
H
OH
25
25
1
1
17
18
94
94
The product 17 was obtained as blue needles (see Section 4.1.5).
The molecular formula C23H26O2 was determined by exact FABMS
spectrum. The IR spectrum showed that a specific band (nmax
3436 cmꢁ1) from a hydroxy group of 17 revealed a low wave-
number shift in comparison with that of 14 (nmax 3452 cmꢁ1). The
1H NMR spectrum showed signals based on a 2-hydroxy-3-
methoxyphenyl and 3-guaiazulenylmethyl group, the signals of
which were carefully assigned using similar analyses to those of 13
(see Tables 2 and 3 and Section 4.1.5). The 13C NMR spectrum
exhibited 22 carbon signals assigned using similar analyses to those
of 13 (see Tables 4 and 5 and Section 4.1.5). Thus, the total spec-
troscopic analyses for 17 led to the molecular structure (3-
guaiazulenyl)(2-hydroxy-3-methoxyphenyl)methane. From com-
ꢀ
ꢀ
(1.405 A) coincided with that of 4BF4 (1.401 A). The bond lengths for
the five-membered ring of the 3-guaiazulenyl group of 14 appre-
0
0
ꢀ
ciably varied between 1.345 and 1.451 A; in particular, the C1 eC2
ꢀ
bond length (1.345 A) was characteristically shorter than the av-
ꢀ
erage CeC bond length for the five-membered ring (1.435 A), the
bond alternation pattern of which coincided with those of 4BF4.
The C30eC
a
bond length of 14 (1.363 A) was also characteristically
ꢀ
0
ꢀ
shorter than the C1eCa bond length of 14 (1.452 A). The C3 eCa
ꢀ
bond length of 14 coincided with that of 4BF4 (1.370 A). The CeC
bond alternation pattern of the 2-hydroxy-3-methoxybenzene ring
of 14 coincided with that of the 2-methoxybenzene ring of 4BF4.
parative studies of the chemical shifts (d
) for the 1H and 13C NMR
The C1eC
a
bond length of 14 was slightly longer than that of 4BF4
ꢀ
signals of 14 with those of 17 (see Tables 2ꢁ5), it can be inferred
that a positive charge of the 3-guaiazulenylmethylium ion unit of
14 is transferred to the 2-hydroxy-3-methoxybenzene and guaia-
zulene rings, generating two representative resonance structures of
the protonated quinonemethide form 14a and the 3-
guaiazulenylium ion form 14b (see Chart 3). From the detailed
comparative NMR studies of 13 with 14 (see Tables 2ꢁ5), it can be
inferred that 13 also possesses similar resonance structures to 14 in
acetonitrile-d3.
(1.443 A). The C1eC2, C2eC3, C6eC1, and C1eC bond lengths of 14
a
were longer than the C3eC4, C4eC5, and C5eC6 bond lengths of 14.
ꢀ
The C2eO bond length (1.354 A) of 14 was slightly shorter than the
ꢀ
C3eO bond length of 14 (1.363 A). The C
a
eH bond length of 14
ꢀ
(0.92 A) coincided with the average CeH bond length for the azu-
lene and benzene rings of 14 (0.91 A). The OeH bond length at the
ꢀ
ꢀ
C2 position was 0.76 A, the bond length of which was character-
istically shorter than that of the oxonium ion H3Oþ (0.86 A), and
5
ꢀ
the CaeH/OeC2 and C2eOH/OeC3 distances of 14 (2.24 and
2.19 A)42 and the space-filling structure of 14 shown in Fig. 2c, along
with the 1H NMR chemical shifts of 14, were suggested to form an
intramolecular CeH/OeH/OeCH3 hydrogen bond between them
(see Fig. 2a). In conclusion, it can be inferred that the total structural
parameters based on the X-ray crystallographic analysis of 14,
compared with those based on the related crystal structure of 4BF4,
apparently led to the crystal structure (3-guaiazulenyl)(2-hydroxy-
3-methoxyphenyl)methylium hexafluorophosphate together with
two representative resonance structures, i.e., the protonated qui-
nonemethide structure 14a and the 3-guaiazulenylium ion struc-
ture 14b, illustrated in Chart 3.
ꢀ
The product 18 was obtained as a blue paste (see Section 4.1.6).
The molecular formula C23H26O2 was determined by exact EIMS
spectrum. The 1H NMR spectrum showed signals based on a 4-
hydroxy-3-methoxyphenyl and 3-guaiazulenylmethyl group, the
signals of which were carefully assigned using similar analyses to
those of 13 (see Tables 2 and 3 and Section 4.1.6). The 13C NMR
spectrum exhibited 22 carbon signals assigned using similar anal-
yses to those of 13 (see Tables 4 and 5 and Section 4.1.6). Thus, the
total spectroscopic analyses for 18 led to the molecular structure (3-
guaiazulenylmethyl)(4-hydroxy-3-methoxyphenyl)methane. The
chemical shifts (d
) for the 1H and 13C NMR signals of 16 compared

S.-i. Takekuma et al. / Tetrahedron 67 (2011) 9719e9728
9723
Fig. 2. (a, b) The ORTEP drawings with numbering schemes of 14, with an equivalent of CH3CN, and 15: 30% probability thermal ellipsoids, respectively. 14: Hydrogen atoms were
refined isotropically. 15: Hydrogen atoms were included but not refined. (c, d) The space-filling structures of 14, with an equivalent of CH3CN, and 15.
Table 7
ꢀ
The selected CeC and CeO bond lengths (A) for the 3-guaiazulenylmethylium ion
results are as follows. The plane of the benzene ring of 15 twisted by
units of 14 and 15, the 2-hydroxy-3-methoxyphenyl group of 14, and the 3,4-
dihydroxyphenyl group of 15
29.5ꢀ from that of the 3-guaiazulenylmethylium ion unit, owing to the
influence of steric hindrance and steric repulsion between the hy-
Atom
14
15
Atom
14
15
drogen atoms of the C6 and C20 positions (see the space-filling
structure of 15 shown in Fig. 2d), the torsion angle of which was
C10eC20
C20eC30
C30eC3a0
C3a0eC40
C40eC50
C50eC60
C60eC70
C70eC80
C80eC8a0
C8a0eC10
C3a0eC8a0
1.345(3)
1.443(4)
1.486(3)
1.411(3)
1.419(3)
1.378(3)
1.403(4)
1.380(4)
1.394(3)
1.450(3)
1.451(3)
1.363(3)
1.349(3)
1.457(3)
1.479(3)
1.396(3)
1.411(3)
1.384(3)
1.398(3)
1.395(3)
1.392(3)
1.456(3)
1.456(3)
1.374(3)
C1eC2
C2eC3
C3eC4
C4eC5
C5eC6
C6eC1
1.406(3)
1.405(3)
1.382(4)
1.383(4)
1.374(4)
1.422(3)
1.452(3)
1.354(3)
1.363(2)
d
1.411(3)
1.378(3)
1.402(2)
1.383(3)
1.380(3)
1.408(2)
1.450(3)
d
larger than that of
7
(22.7ꢀ).32 Similar to 7, the 3-
guaiazulenylmethylium ion unit of 15 clearly underwent bond alter-
nation between single and double bonds as shown inTable 7. The 3,4-
dihydroxybenzene ring of 15 also underwent bond alternation be-
tween single and double bonds as shown in Table 7. The average CeC
bond length fortheseven-membered ringof the3-guaiazulenyl group
C1eC
a
C2eO
C3eO
C4eO
C3OeCH3
d
1.375(2)
1.354(2)
d
ꢀ
ꢀ
of 15 (1.405 A) coincided with that of 7 (1.403 A). The bond lengths for
the five-membered ring of the 3-guaiazulenyl group of 15 appreciably
1.430(3)
d
C30eC
a
d
0
0
ꢀ
varied between 1.349 and 1.456 A; in particular, the C1 eC2 bond
length (1.349 A) was characteristically shorter than the average CeC
ꢀ
ꢀ
bond length for the five-membered ring (1.440 A), the bond alterna-
tionpattern ofwhich coincided with thatof 7. The C30eC
a
bond length
bond
2.4. X-ray crystal structure of 15 compared with those of the
related compounds 2, 7, 19, and 20
ꢀ
of 15 (1.374 A) was alsocharacteristicallyshorter than the C1eC
a
0
ꢀ
length of 15 (1.450 A). The C3 eCa bond length of 15 was slightly
longer than those of 7 and 1943 (1.364 A each); however, the bond
ꢀ
Althoughitwasverydifficulttoobtainasinglecrystalof16 suitable
for X-ray crystallographic analysis, the recrystallization of 15 from
amixedsolventofacetonitrileanddiethylether(1:5,vol/vol)provided
a stable single crystal suitable for that purpose. Thus, the crystal
structure of 15 could be determined by means of X-ray diffraction,
producing accurate structural parameters (see Section 4.1.8). Non-
hydrogen atoms were refined anisotropically and hydrogen atoms
were included but not refined. The ORTEP drawing of 15 with a num-
bering scheme, indicating the structure illustrated inChart 2, isshown
in Fig. 2b along with the selected bond lengths (see Table 7). The
length of which was characteristically shorter than the C30eC7 bond
length of 2043 (1.433 A) (see Chart 4). The C1eC
a
bond length of 15
ꢀ
ꢀ
ꢀ
coincided with those of 7 (1.448 A) and 19 (1.443 A); however, the
bond length of which was longer than that of 210 (1.412 A) and the
ꢀ
ꢀ
C4eC7bond length of 20(1.374 A). The bond alternationpattern of the
3,4-dihydroxyphenyl group of 15 coincided with that of the 4-
ꢀ
methoxyphenyl group of 7. The C4eO bond length (1.354 A) of 15
ꢀ
ꢀ
coincided with those of 7 (1.351 A) and 19 (1.361 A), while the bond
ꢀ
lengthofwhichwasshorterthantheC3eObondlengthof15 (1.375 A).

9724
S.-i. Takekuma et al. / Tetrahedron 67 (2011) 9719e9728
Furthermore, the C4eO bond length of 14 was longer than the cor-
a proton transfer from b to c. The basic studies of our structural
analyses for 13e16 support the existence of the oxonium ion forms
a under the reaction conditions illustrated in Scheme 3.
ꢀ
ꢀ
respondingCeObondlengthsof2(1.318 A)and20 (1.243 A). Similarto
ꢀ
14, the C3eOH/OeC4 distance of 15 (2.14 A) and the space-filling
structure of 15 shown in Fig. 2d were suggested to form
a C3eOH/OeC4 hydrogen bond between them. In conclusion, it can
be inferred that the total structural parameters based on the X-ray
crystallographic analysis of 15, compared with those of the related
compounds 2, 7, 19, and 20, apparently led to the crystal structure (3-
guaiazulenyl)(3,4-dihydroxyphenyl)methylium hexafluorophosphate
together with two representative resonance structures, i.e., the pro-
tonated quinonemethide form 15a and the 3-guaiazulenylium ion
form 15b, illustrated in Chart 3. Along with the experimental results,
the accurate parameters for the crystal structures of 14, with an
equivalent of a recrystallization solvent molecule CH3CN, and 15 were
transferred to a WinMOPAC (Ver. 3.0) program44 and their atomic
charges were calculated. Although the atomic charges of 14 could not
be calculated, those of 15 could be calculated as follows. The order of
larger positive charge for 15 was C-4 (0.223)>C-3 (0.117)>C-6
(0.089)>C-70 (0.082)>C- and C-8a0 (0.064 each)>C-40 (0.035)>C-50
a
(0.024)>C-1 (0.008)>C-3a0 (ꢁ0.004)>C-80 (ꢁ0.007)>C-30 (ꢁ0.016)>
C-60 (ꢁ0.024)>C-10 (ꢁ0.031)>C-20 (ꢁ0.037)>C-2 (ꢁ0.068)>C-5
(ꢁ0.134), the calculation of which suggested the formation of the
resonance structures 15a and 15b illustrated in Chart 3.
Along with the ORTEP drawings and the space-filling structures
of 14 and 15, the top and side views for the packing structures of 14,
with an equivalent of a recrystallization solvent molecule CH3CN,
Scheme 3. A plausible reaction pathway for the formation of 13e16 yielded by the
reactions of 8 with 9e12 in methanol in the presence of hexafluorophosphoric acid
(i.e., 65% aqueous solution) at 25 ꢀC for 2 h.
and 15 revealed that these compounds formed p-stacking structures
in their single crystals, respectively, and showed that each average
inter-plane distance between over-lapping structures [i.e., the 3-
guaiazulenylmethylium plane of a compound and the 2-hydroxy-
3-methoxyphenyl (or 3,4-dihydroxyphenyl) plane of another com-
pound], whichwereoverlapped sothatthose dipole momentsmight
2.6. Electrochemical behavior of 14 and 15
We havebeen interestedfurtherintheelectrochemicalproperties
of 14 and 15, the crystal structures of which could be determined,
with a view to comparative study. The electrochemical behavior of 14
ꢀ
ꢀ
be negated mutually, was 3.46 A for 14 or 3.18 A for 15 (see Fig. 3).
Fig. 3. Top and side views for the packing structures of 14, with an equivalent of CH3CN, and 15, the hydrogen atoms of which are omitted for reasons of clarity.
2.5. A plausible reaction pathway for the formation of 13e16
and 15 was, therefore, measured by means of CV (¼Cyclic Voltam-
mogram) and DPV (¼Differential Pulse Voltammogram) [Potential
(in volts) vs SCE] in CH3CN containing 0.1 M [n-Bu4N]PF6 as a sup-
porting electrolyte. As the results, it was found that 14 and 15 un-
derwent one-electron reduction, respectively, at the potentials of
ꢁ0.33 V (Epc, irreversible) by CV [ꢁ0.26 V (Ep) by DPV] for 14 and
ꢁ0.36 V (Epc, irreversible) by CV [ꢁ0.31 V (Ep) by DPV] for 15, as
shown in Fig. 4, generating the corresponding radical-species45 [i.e.,
From the structures of the resulting products 13e16, a plausible
reaction pathway for the formation of 13e16 can be inferred as il-
lustrated in Scheme 3: namely, the generated oxonium ion forms
a are gradually converted into the target monocarbenium ion
compounds 13e16, presumably via the azulenium ion forms b and
the alkyl oxonium ion forms c, whose structures are yielded by

S.-i. Takekuma et al. / Tetrahedron 67 (2011) 9719e9728
9725
Fig. 4. Cyclic [(a), (c)] and differential pulse [(b), (d)] voltammograms of 14 (3.0 mg, 5.6
mmol) and 15 (3.0 mg, 6.2
m
mol) in 0.1 M [n-Bu4N]PF6, CH3CN (10 mL) at a glassy carbon (ID:
3 mm) and a platinum wire served as working and auxiliary electrodes; scan rates 100 mV sꢁ1 at 25 ꢀC under argon. For comparative purposes, the oxidation potential using
ferrocene as a standard material showed þ0.42 V (Ep) by DPV and þ0.40 V (E1/2) by CV under the same electrochemical measurement conditions as for 14 and 15.
(63% yield) [or (3-guaiazulenyl)(3,4-dihydroxyphenyl)methylium
hexafluorophosphate (15) (43% yield) or (3-guaiazulenyl)(4-hydroxy-
3-methoxyphenyl)methylium hexafluorophosphate (16) (77% yield)],
the products of which are stabilized by 3-guaiazulenyl and dihy-
droxyphenyl (or hydroxymethoxyphenyl) groups; (ii) although the
hydride-reductionsofthe1,2-dihydroxybenzenederivatives13 and15
with NaBH4 in a mixed solvent of ethanol and acetonitrile at 25 ꢀC for
1 h gave several products simultaneously, the hydride-reductions of
the 1-hydroxy-2-methoxybenzene derivatives 14 and 16 with NaBH4
under the same reaction conditions as for 13 and 15 afforded (3-
Chart 1.
guaiazulenyl)(2-hydroxy-3-methoxyphenyl)methane (17) and (3-
the (3-guaiazulenyl)(2-hydroxy-3-methoxyphenyl)methyl and (3-
guaiazulenyl)(3,4-dihydroxyphenyl)methyl radical-species]. Thus,
14 is slightly susceptible to reduction as compared with 15, owing to
guaiazulenyl)(4-hydroxy-3-methoxyphenyl)methane (18) quantita-
tively (94% yield each). Thus, a hydride-ion attached to each HCþ-
a
positionof14 and 16 selectively;(iii)thechemicalshifts (d
)forthe1H
a difference in electron affinity based on each delocalized
p-electron
and 13C NMR signals of 13e16 compared with those of 17 and 18 were
shown in Tables 2ꢁ5, apparently leading to the formation of 13e16
with two representative resonance structures, respectively, i.e., a pro-
system and further, 14 is slightly less susceptible to reduction than 4
[ꢁ0.28 V (Epc, irreversible) by CV (ꢁ0.25 V by DPV)],32 while the re-
duction potential of 15 coincided with that of 7 [ꢁ0.35 V (Epc, irre-
versible) by CV (ꢁ0.29 V by DPV)].32 In conclusion, the facility of one-
electron reduction is in the order of 14>15, the result of which co-
incided with those of 3>625 and of 4>7.32
tonated o- (or p-) benzoquinonemethide form and
a
3-
guaiazulenylium ion form, illustrated in Chart 3; (iv) although it was
very difficult to obtain a single crystal of 13 (and 16) suitable for X-ray
crystallographic analysis, the recrystallization of 14 (and 15) from
a mixed solvent of acetonitrile and diethyl ether provided a stable
single crystal, respectively, suitable for that purpose; (v) similar to the
above NMR spectral results (iii), the structural parameters based on
the X-ray crystallographic analyses of 14 and 15, compared with those
of the related compounds 2, 4BF4, 7, 19, and 20, led to the crystal
structures with two representative resonance structures, respectively,
i.e., a protonated o- (or p-) benzoquinonemethide form and a 3-
guaiazulenylium ion form, illustrated in Chart 3, and further, it could
be inferred that 14 possessed a unique CeH/OeH/OeCH3 intra-
molecular hydrogen bond; and (vi) the reduction potentials of 14 and
15 based on CV and DPV data indicated that the facilityof one-electron
reductionwasintheorderof14>15, theresultofwhichcoincidedwith
those of 3>6 and of 4>7.
3. Conclusion
We have reported the following six interesting points (i)e(vi) in
this paper: namely, (i) the reaction of guaiazulene (8) with 2,3-
dihydroxybenzaldehyde (9) in methanol in the presence of hexa-
fluorophosphoric acid (i.e., 65% aqueous solution) at 25 ꢀC for 2 h
gave (3-guaiazulenyl)(2,3-dihydroxyphenyl)methylium hexafluoro-
phosphate (13) in 86% yield. Similarly, the reaction of 8 with 2-
hydroxy-3-methoxybenzaldehyde (10) [or 3,4-dihydroxybenzal-
dehyde (11) or 4-hydroxy-3-methoxybenzaldehyde (12)] under the
same reaction conditions as for 9 afforded (3-guaiazulenyl)(2-
hydroxy-3-methoxyphenyl)methylium hexafluorophosphate (14)

9726
S.-i. Takekuma et al. / Tetrahedron 67 (2011) 9719e9728
Chart 4.
13
for 1H and 176 MHz for C) cryospectrometer at 25 ꢀC. 1H NMR
spectra were assigned using computer-assisted simulation (soft-
ware: gNMR developed by Adept Scientific plc) on a DELL Di-
mension 9150 personal-computer with a Pentium IV processor.
Cyclic and differential pulse voltammograms were measured by an
ALS Model 600 electrochemical analyzer.
4.1.1. Preparation of (3-guaiazulenyl)(2,3-dihydroxyphenyl)methyl-
ium hexafluorophosphate (13). To
available guaiazulene (8) (70 mg, 0.35 mmol) in methanol (1.0 mL)
was added solution of commercially available 2,3-
a solution of commercially
a
dihydroxybenzaldehyde (9) (55 mg, 0.40 mmol) in methanol
(1.0 mL) containing hexafluorophosphoric acid (65% aqueous so-
lution, 0.2 mL). The mixture was stirred at 25 ꢀC for 2 h, and then
evaporated in vacuo. The obtained residue was recrystallized from
acetonitrile/diethyl ether (1:5, vol/vol) (several times) to provide
pure 13 (150 mg, 0.30 mmol, 86% yield).
Chart 2.
Compound 13: Dark-red powder, mp >149 ꢀC (decomp.); Found:
C, 52.75; H, 4.68%. Calcd for C22H23O4F6P (i.e., C22H23O2þPF6þO2):
C, 53.23; H, 4.67%; IR nmax (KBr) cmꢁ1, 3452 (OeH) and 841, 559
(PFꢁ6 ); exact FABMS (3-nitrobenzyl alcohol matrix), found: m/z
319.1693; calcd for C22H23O2: [MꢁPF6]þ, m/z 319.1693; 700 MHz 1H
NMR (CD3CN), signals based on a (3-guaiazulenyl)methylium ion
structure: 1.45 (6H, d, J¼6.8 Hz, (CH3)2CH-70), 2.50 (3H, d, J¼0.8 Hz,
Me-10), 3.33 (3H, s, Me-40), 3.48 (1H, sept, J¼6.8 Hz, (CH3)2CH-70),
7.99 (1H, br s, H-20), 8.38 (1H, dd, J¼11.3, 2.0 Hz, H-60), 8.48 (1H, d,
J¼11.3 Hz, H-50), 8.57 (1H, d, J¼2.0 Hz, H-80), and 9.00 (1H, br s,
HCþ-
a); signals based on a 2,3-dihydroxyphenyl group: 6.93 (1H, t,
J¼7.8 Hz, H-5), 7.07 (1H, br d, J¼7.8 Hz, H-4), and 7.22 (1H, br d,
J¼7.8 Hz, H-6). The two OH signals at the C-2 and C-3 positions
were included in a signal of slightly existing water molecule in
CD3CN; 176 MHz 13C NMR (CD3CN), 171.0 (C-70), 161.2 (C-8a0), 157.6
(C-40), 153.6 (C-3a0), 150.3 (C-50), 148.2 (C-2) 146.0 (HCþ-
a), 145.7
(C-10), 145.4 (C-1), 144.8 (C-60), 142.1 (C-20), 139.8 (C-80), 139.4 (C-
30), 125.5 (C-6), 124.2 (C-3), 121.8 (C-5), 120.3 (C-4), 40.2 ((CH3)2CH-
70), 29.8 (Me-40), 23.8 ((CH3)2CH-70), and 13.8 (Me-10).
4.1.2. Preparation of (3-guaiazulenyl)(2-hydroxy-3-methoxyphenyl)
methylium hexafluorophosphate (14). To a solution of commercially
available guaiazulene (8) (70 mg, 0.35 mmol) in methanol (1.0 mL)
was added a solution of commercially available 2-hydroxy-3-
methoxybenzaldehyde (10) (61 mg, 0.40 mmol) in methanol
(1.0 mL) containing hexafluorophosphoric acid (65% aqueous so-
lution, 0.2 mL). The mixture was stirred at 25 ꢀC for 2 h, pre-
cipitating the dark-red product 14, and then was centrifuged at
2.5 krpm for 1 min. The crude product thus obtained was carefully
washed with diethyl ether, and was recrystallized from acetonitrile/
diethyl ether (1:5, vol/vol) (several times) to provide pure 14
(118 mg, 0.22 mmol, 63% yield).
Chart 3.
4. Experimental
4.1. General
Melting points were taken on a Yanagimoto MP-S3 instrument.
MS spectra were taken on a JEOL The Tandem Mstation JMS-700
TKM data system. UVevis and IR spectra were taken on a Beck-
man DU640 spectrophotometer and a Shimadzu FTIR-4200 Grating
spectrometer. NMR spectra were recorded with a JNM-ECA500
(500 MHz for 1H and 125 MHz for 13C) or JNM-ECA700 (700 MHz
Compound 14: Dark-red needles, mp >155 ꢀC (decomp.); Found:
C, 56.23; H, 4.91; N, 2.64%. Calcd for
C25H28O3NF6P (i.e.,

S.-i. Takekuma et al. / Tetrahedron 67 (2011) 9719e9728
9727
C23H25O2þPF6þCH3CNþ1/2O2): C, 56.08; H, 5.27; N, 2.62%; UVevis
lmax (CH3CN) nm (log ), 201 (4.47), 216 (4.43), 289 (4.27), 333
(3.98), 362 (4.09), 389 (4.01), and 486 (4.12); IR nmax (KBr) cmꢁ1
C
23H25O2þPF6þCH3CNþO2): C, 54.45; H, 5.11; N, 2.53%; UVevis
3
lmax (CH3CN) nm (log ), 233 (4.42), 307 (4.03), 338 (4.06), and 527
3
,
(4.59); IR nmax (KBr) cmꢁ1, 3468 (OeH) and 841, 559 (PFꢁ6 ); exact
FABMS (3-nitrobenzyl alcohol matrix), found: m/z 333.1861; calcd
for C23H25O2: [MꢁPF6]þ, m/z 333.1855; 700 MHz 1H NMR (CD3CN),
3452 (OeH) and 841, 559 (PFꢁ6 ); exact FABMS (3-nitrobenzyl alco-
hol matrix), found: m/z 333.1834; calcd for C23H25O2: [MꢁPF6]þ, m/
z 333.1855; 700 MHz 1H NMR (CD3CN), signals based on a (3-
guaiazulenyl)methylium ion structure: 1.45 (6H, d, J¼6.9 Hz,
(CH3)2CH-70), 2.50 (3H, d, J¼0.9 Hz, Me-10), 3.33 (3H, s, Me-40), 3.48
(1H, sept, J¼6.9 Hz, (CH3)2CH-70), 8.00 (1H, br s, H-20), 8.38 (1H, dd,
J¼11.2, 2.0 Hz, H-60), 8.47 (1H, d, J¼11.2 Hz, H-50), 8.57 (1H, d,
signals based on a (3-guaiazulenyl)methylium ion structure:
d 1.44
(6H, d, J¼6.8 Hz, (CH3)2CH-70), 2.54 (3H, d, J¼1.0 Hz, Me-10), 3.34
(3H, s, Me-40), 3.46 (1H, sept, J¼6.8 Hz, (CH3)2CH-70), 8.12 (1H, br s,
H-20), 8.35 (1H, dd, J¼11.3, 2.2 Hz, H-60), 8.42 (1H, dd, J¼11.3 Hz, H-
50), 8.57 (1H, d, J¼2.2 Hz, H-80), and 8.72 (1H, br s, HCþ-
a); signals
J¼2.0 Hz, H-80), and 9.02 (1H, br s, HCþ-
a
); signals based on a 2-
based on a 4-hydroxy-3-methoxyphenyl group: d 3.98 (3H, s, MeO-
hydroxy-3-methoxyphenyl group: 3.93 (3H, s, MeO-3), 7.03 (1H, t,
J¼8.1 Hz, H-5), 7.16 (1H, br d, J¼8.1 Hz, H-4), 7.30 (1H, br d, J¼8.1 Hz,
H-6), and 7.58 (1H, br s, HO-2); 176 MHz 13C NMR (CD3CN),171.0 (C-
70), 161.2 (C-8a0), 157.5 (C-40), 153.6 (C-3a0), 150.3 (C-50), 149.2 (C-1),
3), 7.01 (1H, d, J¼8.4 Hz, H-5), 7.45 (1H, br d, J¼1.8 Hz, H-2), 7.50
(1H, dd, J¼8.4, 1.8 Hz, H-6), and 7.69 (1H, br s, HO-4); 176 MHz 13
C
NMR (CD3CN): Ô
d
169.2 (þC-70), 159.6 (C-8a0), 157.1 (C-40), 153.3 (C-
3a0), 153.2 (C-4),151.8 (HC - ),149.2 (C-3),149.0 (C-50),144.6 (C-10),
a
148.6 (C-2), 145.6 (HCþ-
a
), 145.4 (C-10), 144.7 (C-60), 141.9 (C-20),
144.3 (C-60), 141.8 (C-20), 139.6 (C-80), 137.5 (C-30), 130.9 (C-6), 129.0
(C-1), 117.2 (C-5), 117.1 (C-2), 57.0 (MeO-3), 40.1 ((CH3)2CH-70), 30.0
(Me-40), 23.9 ((CH3)2CH-70), and 13.8 (C-10).
139.8 (C-80), 139.4 (C-30), 125.5 (C-6), 123.3 (C-3), 121.6 (C-5), 116.3
(C-4), 57.0 (MeO-3), 40.2 ((CH3)2CH-70), 29.7 (Me-40), 23.7
((CH3)2CH-70), and 13.8 (Me-10).
4.1.5. Reduction of (3-guaiazulenyl)(2-hydroxy-3-methoxyphenyl)
methylium hexafluorophosphate (14) with NaBH4. To a solution of
NaBH4 (20 mg, 0.52 mmol) in ethanol (1.5 mL) was added a solution
of 14 (96 mg, 0.18 mmol) in acetonitrile (2.0 mL). The mixture was
stirred at 25 ꢀC for 1 h, and then was evaporated in vacuo. The
obtained residue was carefully separated by silica gel column
chromatography with hexane/ethyl acetate (9:1, vol/vol) as an el-
uant, and was recrystallized from acetone/distilled water (1:5, vol/
vol) (several times) to provide pure (3-guaiazulenyl)(2-hydroxy-3-
methoxyphenyl)methane (17) (57 mg, 0.17 mmol, 94% yield).
Compound 17: Blue needles [Rf¼0.45 on silica gel TLC
(hexane:AcOEt¼9:1, vol/vol)], mp 118 ꢀC; IR nmax (KBr) cmꢁ1, 3436
(OeH); exact FABMS (3-nitrobenzyl alcohol matrix), found: m/z
334.1939; calcd for C23H26O2: Mþ, m/z 334.1933; 700 MHz 1H NMR
(CD3CN), signals based on a (3-guaiazulenyl)methyl group: 1.31 (6H,
d, J¼6.8 Hz, (CH3)2CH-70), 2.56 (3H, s, Me-10), 2.77 (3H, s, Me-40), 3.03
(1H, sept, J¼6.8 Hz, (CH3)2CH-70), 4.49 (1H, s, CH2-30), 6.80 (1H, d,
J¼10.8 Hz, H-50), 7.28 (1H, dd, J¼10.8, 2.2 Hz, H-60), 7.32 (1H, br s, H-
20), and 8.09 (1H, d, J¼2.2 Hz, H-80); 2-hydroxy-3-methoxyphenyl
4.1.3. Preparation of (3-guaiazulenyl)(3,4-dihydroxyphenyl)methyl-
ium hexafluorophosphate (15). To a solution of commercially avail-
able guaiazulene (8) (70 mg, 0.35 mmol) in methanol (1.0 mL) was
added
a
solution
of
commercially
available
3,4-
dihydroxybenzaldehyde (11) (55 mg, 0.40 mmol) in methanol
(1.0 mL)containinghexafluorophosphoricacid(65% aqueoussolution,
0.2 mL). The mixture was stirred at 25 ꢀC for 2 h, precipitating the
dark-red product 15, and then was centrifuged at 2.5 krpm for 1 min.
The crude product thus obtained was carefully washed with diethyl
ether, and was recrystallized from acetonitrile/diethyl ether (1:5, vol/
vol) (several times) to provide pure 15 (73 mg, 0.15 mmol, 43% yield).
Compound 15: Dark-red blocks, mp >160 ꢀC (decomp.); Found:
C, 54.99; H, 4.57%. Calcd for C22H23O3F6P (i.e., C22H23O2þPF6þ1/
2O2): C, 55.01; H, 4.83%; UVevis lmax (CH3CN) nm (log ) 233 (4.35),
3
306 (3.97), 336 (3.97), and 530 (4.54); IR nmax (KBr) cmꢁ1, 3444,
3274 (OeH) and 844, 559 (PFꢁ6 ); exact FABMS (3-nitrobenzyl alco-
hol matrix), found: m/z 319.1724; calcd for C22H23O2: [MꢁPF6]þ, m/
z 319.1693; 700 MHz 1H NMR (CD3CN), signals based on a (3-
guaiazulenyl)methylium ion structure:Ô
d
1.46 (6H, d, J¼6.8 Hz,
group:Ô
d
3.85 (3H, s, MeO-3), 6.13 (1H, dd, J¼7.8, 1.0 Hz, H-6), 6.57
(CH3)2CH-70), 2.53 (3H, d, J¼0.8 Hz, Me-10), 3.32 (3H, s, Me-40), 3.46
(1H, sept, J¼6.8 Hz, (CH3)2CH-70), 8.09 (1H, s, H-20), 8.35 (1H, dd,
J¼11.3, 2.2 Hz, H-60), 8.42 (1H, dd, J¼11.3 Hz, H-50), 8.56 (1H, d,
(1H, br s, HO-2), 6.63 (1H, t, J¼7.8 Hz, H-5), and 6.78 (1H, dd, J¼7.8,
13
1.0 Hz, H-4); 176 MHz C NMR (CD3CN), 147.6 (C-3), 146.4 (C-40),
143.9 (C-2), 141.7 (C-20), 139.8 (C-70), 138.7 (C-8a0), 135.7 (C-60), 134.2
(C-80),133.9 (C-3a0),130.3 (C-1),126.8 (C-50), 126.4 (C-30) 125.0 (C-10),
122.8 (C-6),120.1 (C-5),109.9 (C-4), 56.7 (MeO-3), 38.2 ((CH3)2CH-70),
31.4 (CH2-30), 26.4 (Me-40), 24.7 ((CH3)2CH-70), and 12.8 (Me-10).
J¼2.2 Hz, H-80), and 8.65 (1H, br s, HCþ-
a); signals based on a 3,4-
dihydroxyphenyl group:Ô 7.04 (1H, d, J¼8.7 Hz, H-5), 7.25 (1H, br s,
HO-3), 7.38 (1H, dd, J¼8.7, 2.2 Hz, H-6), 7.41 (1H, d, J¼2.2 Hz, H-2),
and 7.87 (1H, br s, HO-4); 176 MHz 13C NMR (CD3CN):Ô
d
169.2 (C-
70), 159.6 (C-8a0), 157.1 (C-40), 153.3 (C-3a0), 151.8 (HCþ-
a
), 151.8 (C-
4.1.6. Reduction of (3-guaiazulenyl)(4-hydroxy-3-methoxyphenyl)
methylium hexafluorophosphate (16) with NaBH4. To a solution of
NaBH4 (20 mg, 0.52 mmol) in ethanol (1.5 mL) was added a solution
of 16 (96 mg, 0.17 mmol) in acetonitrile (2.0 mL). The mixture was
stirred at 25 ꢀC for 1 h, and then was evaporated in vacuo. The res-
idue thus obtained was dissolved in hexane and filtered. The hexane
filtrate was evaporated in vacuo, giving a blue paste residue, which
was carefully separated by silica gel column chromatography with
hexane/ethyl acetate (9:1, vol/vol) as an eluant, and was recrystal-
lized from hexane to provide pure (3-guaiazulenyl)(4-hydroxy-3-
methoxyphenyl)methane (18) (55 mg, 0.16 mmol, 94% yield).
Compound 18: Blue paste [Rf¼0.45 on silica gel TLC
(hexane:AcOEt¼9:1, vol/vol)]; exact EIMS (70 eV), found: m/z
334.1963; calcd for C23H26O2: Mþ, m/z 334.1933; 500 MHz 1H NMR
(CD3CN), signals based on a (3-guaiazulenyl)methyl group: 1.30
(6H, d, J¼6.9 Hz, (CH3)2CH-70), 2.56 (3H, s, Me-10), 2.82 (3H, s, Me-
40), 3.02 (1H, sept, J¼6.9 Hz, (CH3)2CH-70), 4.48 (1H, s, CH2-30), 6.80
(1H, d, J¼10.9 Hz, H-50), 7.28 (1H, dd, J¼10.9, 2.3 Hz, H-60), 7.37 (1H,
br s, H-20), and 8.09 (1H, d, J¼2.3 Hz, H-80); signals based on a 4-
hydroxy-3-methoxyphenyl group:Ô 3.73 (3H, s, MeO-3), 6.28
4), 149.0 (C-50), 146.6 (C-3), 146.6 (C-10), 144.3 (C-60), 141.8 (C-20),
139.6 (C-80), 137.5 (C-30), 130.3 (C-6), 129.2 (C-1), 120.1 (C-2), 117.4
(C-5), 40.1 ((CH3)2CH-7), 30.0 (Me-4), 23.9 ((CH3)2CH-7), and 13.8
(Me-1).
4.1.4. Preparation of (3-guaiazulenyl)(4-hydroxy-3-methoxyphenyl)
methylium hexafluorophosphate (16). To a solution of commercially
available guaiazulene (8) (70 mg, 0.35 mmol) in methanol (1.0 mL)
was added a solution of commercially available 4-hydroxy-3-
methoxybenzaldehyde (12) (61 mg, 0.40 mmol) in methanol
(1.0 mL) containing hexafluorophosphoric acid (65% aqueous so-
lution, 0.2 mL). The mixture was stirred at 25 ꢀC for 2 h, pre-
cipitating the dark-red product 16, and then was centrifuged at
2.5 krpm for 1 min. The crude product thus obtained was carefully
washed with diethyl ether, and was recrystallized from acetonitrile/
diethyl ether (1:5, vol/vol) (several times) to provide pure 16
(150 mg, 0.27 mmol, 77% yield).
Compound 16: Dark-red blocks, mp >108 ꢀC (decomp.); Found:
C, 54.60; H, 4.83;
N 2.53%. Calcd for C25H28O4NF6P (i.e.,

9728
S.-i. Takekuma et al. / Tetrahedron 67 (2011) 9719e9728
4. Kozhomuratova, Z. S.; Mironov, Y. V.; Shestopalov, M. A.; Drebushchak, I. V.;
Moroz, N. K.; Naumov, D. Y.; Smolentsev, A. I.; Uskov, E. M.; Fedorov, V. E. Eur. J.
Inorg. Chem. 2007, 2055e2060.
(1H, br s, HO-4), 6.34 (1H, dd, J¼8.0, 2.1 Hz, H-6), 6.66 (1H, d,
J¼8.0 Hz, H-5), and 6.72 (1H, d, J¼2.1 Hz, H-2); 125 MHz 13C NMR
(CD3CN), 148.1 (C-3), 146.4 (C-40), 144.9 (C-4), 141.9 (C-20), 139.9 (C-
70), 138.8 (C-8a0), 136.2 (C-1), 135.7 (C-60), 134.3 (C-80), 133.7 (C-3a0),
127.3 (C-30) 127.0 (C-50), 125.1 (C-10), 121.7 (C-6), 115.4 (C-5), 112.9
(C-2), 56.6 (MeO-3), 38.3 ((CH3)2CH-70), 37.1 (CH2-30), 26.9 (Me-40),
24.7 ((CH3)2CH-70), and 12.9 (Me-10).
5. Fonari, M. S.; Alekseeva, O. A.; Furmanova, N. G.; Lysenko, K. A.; Wang, W.-J.;
ꢁ
Tang, S.-W.; Ganin, E. V.; Gel’mbol’dt, V. O.; Simonov, Y. A. Crystallogr. Rep. 2007,
52, 253e259.
6. Chekhlov, A. N. Russ. J. Gen. Chem. 2008, 78, 1862e1865.
7. Mascal, M.; Hafezi, N.; Meher, N. K.; Fettinger, J. C. J. Am. Chem. Soc. 2008, 130,
13532e13533.
8. Beran, A.; Talla, D.; Losos, Z.; Pinkas, J. Phys. Chem. Miner. 2010, 37, 159e166.
9. The phenolsulfonphthalein 2 is useful as an inspectional agent for kidney
function.
10. Yamaguchi, K.; Tamura, Z.; Maeda, M. Anal. Sci. 1997, 13, 521e522.
11. Ito, S.; Kikuchi, S.; Morita, N.; Asao, T. Chem. Lett. 1996, 175e176.
12. Ito, S.; Kikuchi, S.; Kobayashi, H.; Morita, N.; Asao, T. J. Org. Chem. 1997, 62,
2423e2431.
13. Ito, S.; Kikuchi, S.; Morita, N.; Asao, T. Bull. Chem. Soc. Jpn. 1999, 72, 839e849.
14. Matsubara, Y.; Yamamoto, H.; Nozoe, T. Studies in Natural Products Chemistry
In. Stereoselective Synthesis (Part I); Atta-ur-Rahman, Ed.; Elsevier: Amsterdam,
1994; Vol. 14, pp 313e354.
15. Takekuma, S.; Sasaki, M.; Takekuma, H.; Yamamoto, H. Chem. Lett. 1999,
999e1000.
16. Takekuma, S.; Fukunaga, H.; Takekuma, H.; Yamamoto, H. Chem. Lett. 2000,
662e663.
17. Takekuma, S.; Takata, S.; Sasaki, M.; Takekuma, H. Tetrahedron Lett. 2001, 42,
5921e5924.
18. Takekuma, S.; Jyoujima, S.; Sasaki, M.; Matsumoto, T.; Fukunaga, H.; Takekuma,
H.; Yamamoto, H. Bull. Chem. Soc. Jpn. 2002, 75, 151e152.
19. Takekuma, S.; Tanizawa, M.; Sasaki, M.; Matsumoto, T.; Takekuma, H. Tetrahe-
dron Lett. 2002, 43, 2073e2078.
4.1.7. X-ray crystal structure of (3-guaiazulenyl)(2-hydroxy-3-
methoxyphenyl)methylium hexafluorophosphate (14). The X-ray
measurement of the single crystal 14 was made on a Rigaku Saturn
CCD area detector with graphite monochromated Mo Ka radiation
ꢀ
(l
¼0.71075 A) at ꢁ160ꢂ1 ꢀC. The structure was solved by direct
methods (SIR92) and expanded using Fourier techniques (DIR-
DIF99). The non-hydrogen atoms were refined anisotropically.
Hydrogen atoms were refined isotropically. The final cycle of full-
matrix least-squares refinement was based on F2. All calculations
were performed using the CrystalStructure crystallographic soft-
ware package developed by Rigaku corporation, Japan. Crystallo-
graphic data have been deposited with Cambridge Crystallographic
Data Center: Deposition number CCDC-760635 for compound No.
14. Copies of the data can be obtained free of charge via http://
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge
Crystallographic Data Center, 12, Union Road, Cambridge, CB2 1EZ,
UK; fax: þ44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk).
Crystallographic data for 14: C25H29O2NF6P (FW¼520.47), dark-
red needle (crystal size, 0.50ꢃ0.24ꢃ0.20 mm3), monoclinic, P21/n
20. Sasaki, M.; Nakamura, M.; Hannita, G.; Takekuma, H.; Minematsu, T.; Yoshihara,
M.; Takekuma, S. Tetrahedron Lett. 2003, 44, 275e279.
21. Sasaki, M.; Nakamura, M.; Uriu, T.; Takekuma, H.; Minematsu, T.; Yoshihara, M.;
Takekuma, S. Tetrahedron 2003, 59, 505e516.
22. Nakamura, M.; Sasaki, M.; Takekuma, H.; Minematsu, T.; Takekuma, S. Bull.
Chem. Soc. Jpn. 2003, 76, 2051e2052.
23. Takekuma, S.; Sasaki, K.; Nakatsuji, M.; Sasaki, M.; Minematsu, T.; Takekuma, H.
Bull. Chem. Soc. Jpn. 2004, 77, 379e380.
24. Nakatsuji, M.; Hata, Y.; Fujihara, T.; Yamamoto, K.; Sasaki, M.; Takekuma, H.;
Yoshihara, M.; Minematsu, T.; Takekuma, S. Tetrahedron 2004, 60,
5983e6000.
ꢀ
ꢀ
ꢀ
(#14), a¼7.841(2) A, b¼24.749(7) A, c¼13.135(4) A,
b
¼108.145(5)ꢀ,
V¼2422.3(12) A , Z¼4, Dcalcd¼1.427 g/cm3,
m
(Mo K
a
)¼1.830 cmꢁ1
,
3
ꢀ
measured reflections¼22,903, observed reflections¼10,256, No. of
variables¼569, R1¼0.0644, wR2¼0.1438, and goodness of fit
indicator¼0.970.
25. Takekuma, S.; Hata, Y.; Nishimoto, T.; Nomura, E.; Sasaki, M.; Minematsu, T.;
Takekuma, H. Tetrahedron 2005, 61, 6892e6907.
26. Takekuma, S.; Takahashi, K.; Sakaguchi, A.; Shibata, Y.; Sasaki, M.; Minematsu,
T.; Takekuma, H. Tetrahedron 2005, 61, 10349e10362.
27. Takekuma, S.; Takahashi, K.; Sakaguchi, A.; Sasaki, M.; Minematsu, T.; Take-
kuma, H. Tetrahedron 2006, 62, 1520e1526.
28. Takekuma, S.; Hirosawa, M.; Morishita, S.; Sasaki, M.; Minematsu, T.; Take-
kuma, H. Tetrahedron 2006, 62, 3732e3738.
29. Takekuma, S.; Sonoda, K.; Fukuhara, C.; Minematsu, T. Tetrahedron 2007, 63,
2472e2481.
30. Takekuma, S.; Tone, K.; Sasaki, M.; Minematsu, T.; Takekuma, H. Tetrahedron
2007, 63, 2490e2502.
31. Takekuma, S.; Mizutani, K.; Inoue, K.; Nakamura, M.; Sasaki, M.; Minematsu, T.;
Sugimoto, K.; Takekuma, H. Tetrahedron 2007, 63, 3882e3893.
32. Takekuma, S.; Tamura, M.; Minematsu, T.; Takekuma, H. Tetrahedron 2007, 63,
12058e12070.
33. Takekuma, S.; Hori, S.; Minematsu, T.; Takekuma, H. Bull. Chem. Soc. Jpn. 2008,
81, 1472e1484.
34. Takekuma, S.; Hori, S.; Minematsu, T.; Takekuma, H. Res. Lett. Org. Chem. 2009, ,
doi:10.1155/2009/684359 Article ID 684359, 5 pages (open access article).
35. Takekuma, S.; Ijibata, N.; Minematsu, T.; Takekuma, H. Bull. Chem. Soc. Jpn.
2009, 82, 585e593.
36. Takekuma, S.; Fukuda, K.; Kawase, Y.; Minematsu, T.; Takekuma, H. Bull. Chem.
Soc. Jpn. 2009, 82, 879e890.
4.1.8. X-ray crystal structure of (3-guaiazulenyl)(3,4-
dihydroxyphenyl)methylium hexafluorophosphate (15). The X-ray
measurement of the single crystal 15 was made on a Rigaku Saturn
CCD area detector with graphite monochromated Mo Ka radiation
ꢀ
(l
¼0.71075 A) at ꢁ170ꢂ1 ꢀC. The structure was solved by direct
methods (SIR92) and expanded using Fourier techniques (DIRDIF99).
The non-hydrogen atoms were refined anisotropically. Hydrogen
atoms were included but not refined. The final cycle of full-matrix
least-squares refinement was based on F2. All calculations were per-
formed using the CrystalStructure crystallographic software package
developed by Rigaku corporation, Japan. Crystallographic data have
been deposited with Cambridge Crystallographic Data Center: De-
position number CCDC-768569 for compound No. 15.
Crystallographic data for 15: C22H23O2F6P (FW¼464.39), dark-red
block (crystal size, 0.58ꢃ0.16ꢃ0.10 mm3), monoclinic, P21/n (#14),
ꢀ
ꢀ
ꢀ
a¼7.6506(17) A, b¼27.259(6) A, c¼10.119(2) A,
b
¼108.565(4)ꢀ,
3
V¼2000.5(7) A , Z¼4, Dcalcd¼1.542 g/cm3,
m
(Mo K
a
)¼2.100 cmꢁ1
,
ꢀ
37. Takekuma, S.; Fukuda, K.; Minematsu, T.; Takekuma, H. Bull. Chem. Soc. Jpn.
measured reflections¼18,948, observed reflections¼3466, No. of
variables¼304, R1¼0.0465, wR2¼0.1261, and goodness of fit
indicator¼1.210.
2009, 82, 1398e1408.
38. Takekuma, S.; Matsuoka, H.; Minematsu, T.; Takekuma, H. Tetrahedron 2010, 66,
3004e3015.
39. Takekuma, S.; Matsuoka, H.; Minematsu, T.; Takekuma, H. Bull. Chem. Soc. Jpn.
2010, 83, 1248e1263.
40. Takekuma, S.; Kaibara, M.; Minematsu, T.; Takekuma, H. Tetrahedron 2011, 67,
4780e4792.
Acknowledgements
41. The crystal structure of 4 (see Chart 2) could not be determined because of
difficulty in obtaining a single crystal suitable for X-ray crystallographic anal-
ysis, while the crystal structure of 4BF4 could be determined.32
This work was partially supported by a Grant-in-Aid for Scien-
tific Research from the Ministry of Education, Culture, Sports, Sci-
ence and Technology, Japan.
ꢀ
42. The van der Waals radii of hydrogen and oxygen atoms are 1.2 and 1.4 A re-
spectively. Therefore, the CaeH/OeC2 and C2eOH/OeC3 distances of 14 are
ꢀ
shorter than the sum of the above radii (2.6 A).
€
43. Laus, G.; Schottenberger, H.; Wurst, K.; Schutz, J.; Ongania, K.-H.; Horvath, U. E.
References and notes
€
I.; Schwarzler, A. Org. Biomol. Chem. 2003, 1, 1409e1418.
44. The computer program was developed by Fujitsu Ltd., Japan. The keywords (1
SCF, PRECISE, VECTORS, ALLVEC, BONDS, PM3, and CHARGE¼1) were used.
45. In the previous paper,25 we proposed a redox mechanism based on the CV and
1. Barbour, L. J.; MacGillivray, L. R.; Atwood, J. L. J. Chem. Crystallogr. 1996, 26, 59e61.
2. Hammerschmidt, A.; Beckmann, I.; Lage, M.; Krebs, B. Z. Anorg. Allg. Chem. 2005,
631, 393e396.
€
DPV
data
of
(3-guaiazulenyl)[4-(methoxycarbonyl)phenyl]methylium
hexafluorophosphate.
3. Farrell, D.; Harding, C. J.; McKee, V.; Nelson, J. Dalton Trans. 2006, 3204e3211.