Preparation, crystal structure, and spectroscopic, chemical, and electrochemical properties of (2E,4E)-4-[4-(dimethylamino)phenyl]-1-(3-guaiazulenyl)-1,3-butadiene compared with those of (E)-2-[4-(dimethylamino)phenyl]-1-(3-guaiazulenyl)ethylene

Article abstract of DOI:10.1016/j.tet.2010.02.064

Wittig reaction of 3-[4-(dimethylamino)phenyl]propanal (5) with (3-guaiazulenylmethyl)triphenylphosphonium bromide (4) in ethanol containing NaOEt at 25 °C for 24 h under argon gives the title (2E,4E)-1,3-butadiene derivative 6E in 19% isolated yield. Spe

Full text of DOI:10.1016/j.tet.2010.02.064

Tetrahedron 66 (2010) 3004–3015
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Preparation, crystal structure, and spectroscopic, chemical, and electrochemical
properties of (2E,4E)-4-[4-(dimethylamino)phenyl]-1-(3-guaiazulenyl)-
1,3-butadiene compared with those of (E)-2-[4-(dimethylamino)phenyl]-
1-(3-guaiazulenyl)ethylene
,
a
b
a
Shin-ichi Takekuma a , Hiroto Matsuoka , Toshie Minematsu , Hideko Takekuma
*
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:
Wittig reaction of 3-[4-(dimethylamino)phenyl]propanal (5) with (3-guaiazulenylmethyl)triphenyl-
phosphonium bromide (4) in ethanol containing NaOEt at 25 ꢀC for 24 h under argon gives the title
(2E,4E)-1,3-butadiene derivative 6E in 19% isolated yield. Spectroscopic properties, crystal structure, and
Received 3 December 2009
Received in revised form 16 February 2010
Accepted 17 February 2010
Available online 21 February 2010
electrochemical behavior of the obtained new extended
p-electron system 6E, compared with those of
the previously reported (E)-2-[4-(dimethylamino)phenyl]-1-(3-guaiazulenyl)ethylene (12), are docu-
mented. Furthermore, reaction of 6E with 1,1,2,2-tetracyanoethylene (TCNE) in benzene at 25 ꢀC for 24 h
under argon affords a new Diels–Alder adduct 8 in 59% isolated yield. Along with spectroscopic prop-
Keywords:
(2E,4E)-1,3-Butadiene derivative
Crystal structures
erties of the [
p
4þ
p2] cycloaddition product 8, the crystal structure, possessing a cis-3,6-substituted
1,1,2,2-tetracyano-4-cyclohexene unit, is shown. Moreover, reaction of 6E with (E)-1,2-dicyanoethylene
(DCNE) under the same reaction conditions as the above gives no product; however, this reaction in
p-xylene at reflux temperature (138 ꢀC) for four days under argon affords a new Diels–Alder adduct 9 in
54% isolated yield. Although reaction of 6E with DCNE in toluene at reflux temperature (110 ꢀC) for four
days under argon provides 9 very slightly, reaction of 6E with dimethyl acetylenedicarboxylate (DMAD)
in toluene at reflux temperature for two days under argon yields a new Diels–Alder adduct 10, in 58%
isolated yield, which upon oxidation with MnO2 in CH2Cl2 at 25 ꢀC for 1 h gives 11, converting
a (CH3)2N-400 into CH3NH-400 group, in 37% isolated yield. The crystal structure of 11 supports the mo-
lecular structure 10 possessing a partial structure cis-3,6-substituted 1,2-dimethoxycarbonyl-1,4-cyclo-
hexadiene. The title basic studies on the above are reported in detail.
Diels–Alder adducts
Extended
p-electron system
Guaiazulene
Properties
Wittig reaction
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
possessing interesting molecular structures, selectively. Similar to
our products 18–21, in 2009 Shoji et al. reported that the reaction of
In the previous papers,1–22 we reported facile preparation and
crystal structures as well as spectroscopic, chemical, and electro-
1,3,6-tri-tert-butylazulene with TCNE in ethyl acetate at room
temperature for 15 h gave 3,5,9-tri-tert-butyltricyclo[6.2.2.02,6]-
dodeca-2,4,6,9-tetraene-11,11,12,12-tetracarbonitrile,23 quantita-
tively, whose proposed reaction mechanism was quoted from our
chemicalpropertiesofnewconjugatedp-electronsystemspossessing
a
3-guaiazulenyl (¼5-isopropyl-3,8-dimethylazulen-1-yl)1–16,18–22
[or an azulen-1-yl8,15 or
a
3-(methoxycarbonyl)azulen-1-yl17
]
literature.12 Furthermore, in relation to the conjugated
p-electron
group. During the course of our basic and systematic investigations
on azulenes, we found that 12,18 13,18 and 14–178 (see Chart 1) serve
as strong two-electron donors and one-electron acceptors (or a two-
electron acceptor for 17), respectively, and further, that the reactions
of 12, 13, 16, and 17 with 2 equiv of TCNE, which serves as a strong
electron acceptor,11,12 in benzene at 25 ꢀC for 24 h under argon give
unique cycloaddition products 18,18 19,18 20,12 and 2112 (see Chart 2),
systems 12–17, for example, preparation and anticancer activity of
(E)-1-aryl-2-(3-guaiazulenyl)ethylenes and (2E,4E)-1-aryl-4-(3-
guaiazulenyl)-1,3-butadienes have been reported24 and moreover,
preparation and anticoccidial activity,25 quadratic nonlinear optical
properties,26,27 fluorescence properties,28–30 and functional dyes31
of (E)-1-aryl-2-[4-(dimethylamino)phenyl]ethylenes and (2E,4E)-
1-aryl-4-[4-(dimethylamino)phenyl]-1,3-butadienes have been
studied to a considerable extent; however, none have really been
documented for the accurate crystal structures as well as the de-
tailed spectroscopic, chemical, and electrochemical properties of
* Corresponding author. Tel.: þ81 6 6721 2332x5222; fax: þ81 6 6727 2024.
E-mail address: takekuma@apch.kindai.ac.jp (S.-i. Takekuma).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.02.064

S.-i. Takekuma et al. / Tetrahedron 66 (2010) 3004–3015
3005
Chart 1.
Chart 2.
those compounds. Along with the above basic studies,1–31 our next
challenge has quite recently been focused on the following clarifi-
cation: namely, (i) preparation, crystal structure, and characteristic
formation of the resulting product. We now wish to report the de-
tailed studies on clarification of the above (i)–(iii) with a view to
comparative study and further, on the reactions of 6E with DCNE
(and DMAD) compared with the reaction of 6E with TCNE.
properties of the title new extended p-electron system 6E (see Chart
1) compared with those of 12. Especially, compound 6E, formed by
the C, H, N elements, can be expected to serve as a more strong two-
electron donor in comparison with 12 and a similar one-electron
acceptor to 12, whose phenomena are noteworthy as an organic
electronic material; (ii) a plausible redox mechanism based on the
redox potentials of 6E, compared with those of 12, by means of cyclic
voltammogram (CV) and differential pulse voltammogram (DPV);
and (iii) the reaction of 6E with TCNE under the same reaction
conditions as for 12 and a plausible reaction pathway for the
2. Results and discussion
2.1. Preparation and spectroscopic properties of 6E compared
with those of 12
In 2008 we reported preparation, crystal structure, and spectro-
scopic, chemical, and electrochemical properties of the 4-(dimethyl-
amino)phenyl-
and
3-guaiazulenyl-substituted
(E)-ethylene

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S.-i. Takekuma et al. / Tetrahedron 66 (2010) 3004–3015
Scheme 1. The preparation of the Wittig reagent 4 and the reaction of 5 with 4 in ethanol in the presence of sodium ethoxide at 25 ꢀC for 24 h under argon.
derivative 1218 (12% isolated yield) (see Chart 1) in detail. For com-
parative purposes, the 4-(dimethylamino)phenyl- and 3-guaiazu-
lenyl-substituted (2E,4E)-1,3-butadiene derivative 6E was prepared,
in19%isolatedyield, usingtheWittigreactionshowninScheme1. The
molecular structure of 6E was established on the basis of spectro-
scopic data [UV–vis, IR, exact EIMS, and 1H and 13C NMR including 2D
NMR (i.e., H–H COSY, HMQC, and HMBC)]. Similar to 12, the geo-
metrical isomer of 6E, i.e., (2Z,4E)-4-[4-(dimethylamino)phenyl]-1-
(3-guaiazulenyl)-1,3-butadiene (6Z), was observed by the silica gel
TLC analysis of the reaction mixture,32 while it could not be isolated
using silica gel column chromatography and recrystallization. The
molecular structure of 6Z could be determined by the 1H NMR spec-
tral analysis of a mixture of 6E and 6Z.32
resembled that of 12; however, the longest absorption wavelength
of 6E revealed a slight bathochromic shift ( 5 nm) and a slight
hypochromic effect ( log
¼0.03) in comparison with that of 12
(see Fig. 1). These visible data corresponded to the D p-HOMO–
D
D
3
p
-
LUMO/eV energy levels33,34 of 6E and 12 (see Table 1). The IR
spectrum showed specific bands based on the C–H, –HC]CH–,
C]C, and C–N bonds, the wavenumbers of which revealed slight
high and low wavenumber shifts in comparison with those of 12.
The molecular formula C27H31N was determined by exact EIMS
spectrum. The 1H NMR spectrum showed signals based on
a 3-guaiazulenyl and 4-(dimethylamino)phenyl group and signals
based on a (2E,4E)-1,3-butadiene unit possessing two substituents
at the C-1 and C-4 positions, the signals of which were carefully
assigned using H–H COSY and computer-assisted simulation based
on first-order analysis. Although the proton signals (H-200,600 and
H-1) of 6E showed apparently up-field shifts in comparison with
those of 12, the other signals of 6E coincided with those of 12. The
The target compound 6E was obtained as black plates, while
a solution of 6E in CH2Cl2 was green. The spectroscopic properties
of 6E compared with those of 12 are described as follows. The UV–
vis spectrum of 6E showed that the spectral pattern of 6E
Figure 1. The UV–vis spectra of 6E (a) and 12 (b) in CH2Cl2. Concentrations, 6E: 0.11 g Lꢁ1(298 mol), 12: 0.10 g Lꢁ1(291
m mmol). Length of the Cell, 0.1 cm each. Each log 3 value is
given in parenthesis.

S.-i. Takekuma et al. / Tetrahedron 66 (2010) 3004–3015
3007
Table 1
3-guaiazulenylium and p-benzoquinodimethane monoiminium
ions.18 Along with the experimental results, the accurate parameters
for the crystal structures of 6EB and 12 were transferred to a Win-
The dipole moments,33,34 the -LUMO energy levels,33,34 the longest
p-HOMO and p
wavelength absorption maxima, and the redox potentialsa of 6E and 12
MOPAC (Ver. 3.0) program34 and their dipole moments and
p-
Compound Dipole
moment/D
1.963
1.718
p-HOMO/eV p-LUMO/eV D p-HOMO–p-LUMO/eV
HOMO–p
-LUMO energy levels were calculated,33 each value of
6E
12
ꢁ7.361
ꢁ7.464
ꢁ1.056
ꢁ1.033
ꢁ6.305
ꢁ6.431
which was shown inTable 1. From the calculation, it is suggested that
the dipole moment of 6EB (1.963 debye) is larger than that of 12
(1.718 debye), and that the D p-HOMO–p
-LUMO energy level of 6EB
Compound
lmax/nm (log
3)
E1OX/V
E2OX/V
E1red/V
(ꢁ6.305 eV) is smaller than that of 12 (ꢁ6.431 eV), the values of
which coincide with the difference between the longest visible
absorption wavelength of 6E and that of 12.
6E
12
659 (2.77)
654 (2.80)
0.30
0.33
0.30
0.46
ꢁ1.70
ꢁ1.68
a
CV data.
2.3. Electrochemical behavior of 6E compared with that of 12
13C NMR spectrum exhibited 23 carbon signals assigned using
HMQC and HMBC. Although the carbon (C-30 and C-100) and carbon
(C-1 and C-2) signals of 6E showed apparently up- and down-field
shifts in comparison with those of 12, the other signals of 6E co-
incided with those of 12. Thus, the spectroscopic data for 6E led to
the molecular structure illustrated in Chart 1.
The electrochemical property of 6E was measured by means of
CV and DPV [Potential (in volt) vs. SCE] in CH3CN containing 0.1 M
[n-Bu4N]BF4 as a supporting electrolyte. Two redox potentials ob-
served by DPV were positioned at the Ep values of þ0.31 and
ꢁ1.68 V, whose currents showed 57.6 and 31.3
mA, and the corre-
sponding two reversible redox potentials determined by CV were
located at the values of þ0.30 (E1/2) and ꢁ1.70 V (E1/2) as shown in
Figures 3a and b. The result of the DPV datum [i.e., the ratio of each
2.2. X-ray crystal structure of 6E compared with that of 12
current (in mA) of the two redox potentials] showed that 6E served
The recrystallization of 6E from a mixed solvent of chloroform
and methanol (1:5, vol/vol) provided stable single crystals suitable
for X-ray crystallographic analysis. The crystal structure of 6E was
then determined by means of X-ray diffraction, producing accurate
structural parameters. As a result, two molecules of 6E were found to
exist in the unit cell of the crystal. The different views of the two
ORTEP drawings (6EA and 6EB) with a numbering scheme are shown
in Figures 2a and b. Similar to 12, the crystal structures of 6EA and 6EB
supported the molecular structure (see Chart 1) established on the
basis of spectroscopic data. Previously, it was found that the aromatic
rings of the 400-(dimethylamino)phenyl and 30-guaiazulenyl groups
of 12 twisted by 1ꢀ and 23ꢀ from the plane of the trans–HC]CH–
unit, presumably due to the influence of inter-molecular stacking.18
Similar to 12, each plane of the 30-guaiazulenyl group, the C1–C2
part, and the C3–C4 part twisted by 17ꢀ, 1ꢀ, and 8ꢀ (for 6EA) and 12ꢀ,
8ꢀ, and 13ꢀ (for 6EB), respectively, from each plane of the C1–C2 part,
the C3–C4 part, and the 400-(dimethylamino)phenyl group, owing to
a similar reason to that of 12. The structural parameters of 6EA and
6EB showed that the average C–C bond lengths for the seven- and
five-membered rings of the 3-guaiazulenyl groups of 6EA (1.410 and
1.429 Å) and 6EB (1.409 and 1.429 Å) coincided with those of 12
(1.407 and 1.425 Å). The C1–C2 and C3–C4 bond lengths of 6EA and
6EB were longer than the C1–C2 bond length of 12. The bond alter-
nation pattern observed for the 3-guaiazulenyl and 4-(dimethyl-
amino)phenyl groups of 6EA and 6EB coincided with that of 12,
suggesting a small contribution of the resonance structures of the
as a two-electron donor and a one-electron acceptor. Furthermore,
it was found that the reduction potential of 6E coincided with that
of 12, and that 6E underwent two-electron oxidation simulta-
neously, while 12 underwent stepwise two-electron oxidation.18
The reduction potentials of 6E and 12 corresponded to their
p
-LUMO/eV energy levels and the oxidation potentials of 6E and 12
corresponded to their -HOMO/eV energy levels (see Table 1).
Referring the -HOMO and -LUMO distribution diagrams on the
p
p
p
ball and stick molecular structure of 6EB (see Fig. 4a and b)33,34
compared with those of 12 (Figs. 4c and d),33,34 a plausible redox
mechanism of 6E based on CV and DPV data can be inferred as il-
lustrated in Scheme 2: namely, 6E undergoes two-electron oxida-
tion at a potential of þ0.30 V (E1/2) by CV (þ0.31 V by DPV),
generating an electrochemically stable dication 6c via the cation-
radical 6a and 6b. Along with the oxidation potential, 6E is re-
duced to the anion-radical 6d at a potential of ꢁ1.70 V (E1/2) by CV
(ꢁ1.68 V by DPV). In conclusion, we clarified that 6E serves as
a more strong two-electron donor in comparison with 12 and
a similar one-electron acceptor to 12.
2.4. Reaction of 6E with TCNE
In 2008 we reported that the reaction of 12 with 2 equiv of TCNE
in benzene at 25 ꢀC for 24 h under argon gave a product 18 (see
Chart 2) in 41% isolated yield and further, a plausible reaction
Figure 2. The different views of the ORTEP drawings, with a numbering scheme (30% probability thermal ellipsoids), of 6EA and 6EB.

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S.-i. Takekuma et al. / Tetrahedron 66 (2010) 3004–3015
pathway for the formation of 18 was proposed. Along with the
spectroscopic properties of 18, the crystal structure of 18 was de-
termined.18 For comparative purposes, the reaction of 6E with
2 equiv of TCNE was carried out under the same reaction conditions
as for 1218 (see Scheme 3), affording a new [
p4þ
p2] cycloaddition
product 835 in 59% isolated yield, the molecular structure of which
was established on the basis of similar spectroscopic analyses to
those of 6E. This reaction did not give a structurally unique product
7 (see Scheme 3), which is a similar adduct to 18–21 (see Chart 2).
Compound 8 was obtained as blue plates. The characteristic UV–
vis absorption bands of 6E were not observed, while those based on
guaiazulene36 (¼7-isopropyl-1,4-dimethylazulene) (1) with two
bands (434 and 453sh nm) were observed as shown in Figure 5 and
the longest visible absorption wavelength appeared at lmax 592 nm
(log
3¼2.68). The IR spectrum showed specific bands from the C–H,
C^N, C]C, and C–N bonds. The molecular formula C33H31N5 was
determined by exact FABMS spectrum. The 1H NMR (including
NOE) spectrum showed signals based on a 4-(dimethylamino)-
phenyl and 3-guaiazulenyl group and a cis-3,6-substituted 1,1,2,2-
tetracyano-4-cyclohexene unit, the signals of which were carefully
assigned using conventional methodology. The 13C NMR spectrum
exhibited 38 carbon signals assigned using HMQC and HMBC. Thus,
the spectroscopic data for 8 led to the molecular structure illus-
trated in Scheme 3. In relation to our study, in 1990 O’Shea and
Foote reported that the reaction of (2E,4E)-hexadiene with TCNE in
CH2Cl2 at 25 ꢀC yielded the Diels–Alder adduct 1,1,2,2-tetracyano-
cis-3,6-dimethyl-4-cyclohexene, quantitatively (>99.5% yield),37
the partial structure cis-3,6-substituted 1,1,2,2-tetracyano-4-cyclo-
hexene, established on the basis of 1H NMR spectral analysis, of
which coincided with that of 8.
The recrystallization of 8 from a mixed solvent of ethyl acetate
and hexane (1:5, vol/vol) provided stable single crystals suitable for
X-ray crystallographic analysis. The crystal structure of 8 was then
determined by means of X-ray diffraction, producing accurate
structural parameters. As a result, a molecule of the cis-3,6-
substituted form 8 with an equivalent of AcOEt molecule was found
to exist in the unit cell of the crystal. The ORTEP drawing with
Figure 3. Cyclic and differential pulse voltammograms of 6E (2.9 mg, 7.8 mmol) [see
(a), (b)] in 0.1 M [n-Bu4N]BF4, CH3CN (10 mL) at a glassy carbon (ID: 3 mm) and
platinum wire served as the working and auxiliary electrodes; scan rates
100 mV sꢁ1at 25 ꢀC under argon. For comparative purposes, the oxidation potential
a
using ferrocene as a standard material showed þ0.45 V (Ep) by DPV and þ0.42 V (E1/2
)
by CV under the same electrochemical measurement conditions as for 6E.
Figure 4. The
p-HOMO and p-LUMO energy levels of 6E [see (a), (b)] and 12 [see (c), (d)], and their distribution diagrams on the ball and stick molecular structures of 6E [see (a),
(b)] and 12 [see (c), (d)].

S.-i. Takekuma et al. / Tetrahedron 66 (2010) 3004–3015
3009
Scheme 2. A plausible redox mechanism based on the CV and DPV data of 6E and the
p-HOMO–p-LUMO distribution diagrams on the ball and stick molecular structure of 6E.
of TCNE in benzene was added a solution of 12 (or 13) in benzene
under argon, turning the green solution of 12 (or 13) into a black
solution, rapidly. The result suggested that the reaction of 12 (or 13)
with TCNE gave the corresponding charge-transfer (CT) complex a.
Following addition, the reaction mixture was stirred at 25 ꢀC for
24 h under argon, gradually precipitating a white solid of 18 (or 19).
As it so happens, azulenes are insusceptible to Diels–Alder re-
action.38 Thus, these results suggested that the CT complex a was
converted to 18 (or 19), presumably via the biradical b, the in-
termediate c, and the [
p
4þ
p
2] cycloaddition of c with TCNE.18
For a comparative purpose, we now propose a plausible reaction
pathway for the formation of 8 according to the following experi-
mental results: namely, to a solution of TCNE in benzene was added
a solution of 6E in benzene under argon, turning the green solution
of 6E into a blue solution of 8, rapidly. From the visible spectra of
this reaction shown in Figure 7, a plausible reaction pathway for
formation can be inferred that compound 8 is produced pre-
sumably via the Diels–Alder (i.e., the [
action of 6E with TCNE (see Scheme 3).
p4þp2] cycloaddition) re-
Scheme 3. The reaction of 6E with 2 equiv of TCNE in benzene at 25 ꢀC for 24 h under
argon.
a numbering scheme, indicating the molecular structure 8 illus-
trated in Scheme 3, is shown in Figure 6.
2.5. A plausible reaction pathway for the formation of 8
In 2008 we proposed a plausible reaction pathway for the for-
mation of 18 and 19 illustrated in Scheme 4:18 namely, to a solution
Figure 6. The ORTEP drawing, with a numbering scheme (30% probability thermal
ellipsoids), of 8 possessing an equivalent of AcOEt molecule. The selected bond lengths
(Å) of 8 are as follows: C1–C2; 1.389(3), C2–C3; 1.428(3), C3–C3a; 1.416(2), C3a–C4;
1.411(2), C4–C10; 1.517(3), C4–C5; 1.402(3), C5–C6; 1.391(3), C6–C7; 1.396(3), C7–C11;
1.528(3), C11–C12; 1.521(4), C11–C13; 1.529(4), C7–C8; 1.403(3), C8–C8a; 1.386(3),
C8a–C1; 1.419(3), C1–C9; 1.499(3), C3a–C8a; 1.500(2), C10–C70; 1.498(3), C70–N80;
1.132(3), C10–C90; 1.477(3), C90–N100; 1.122(2), C10–C20; 1.594(3), C20–C110; 1.479(3),
C110–N120; 1.136(4), C20–C130; 1.497(4), C130–N140; 1.135(4), C20–C30; 1.576(3), C30–C40;
1.505(3), C40–C50; 1.332(3), C50–C60; 1.508(2), C60–C10; 1.620(3), C60–C3; 1.491(3), C30–
C100; 1.517(3), C100–C200; 1.393(3), C200–C300; 1.389(3), C300–C400; 1.414(3), C400–N700;
1.369(3), N700–C800; 1.443(3), N700–C900; 1.445(3), C400–C500; 1.412(3), C500–C600; 1.386(3),
and C600–C100; 1.402(3).
Figure 5. The UV–vis spectrum of 8 in benzene. Concentration, 8 with an equivalent of
AcOEt molecule: 0.14 g Lꢁ1(239
given in parenthesis.
mmol). Length of the Cell, 0.1 cm. Each log 3 value is

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S.-i. Takekuma et al. / Tetrahedron 66 (2010) 3004–3015
Scheme 4. A plausible reaction pathway for the formation of 18 (or 19).
while those based on guaiazulene36 were observed as shown in
Figure 8 and the longest visible absorption wavelength appeared at
lmax 609 nm (log
¼2.78). The IR spectrum showed specific bands
3
from the C–H, C^N, C]C, and C–N bonds. The molecular formula
C31H33N3 was determined by exact FABMS spectrum. The 1H NMR
spectrum showed signals based on a 4-(dimethylamino)phenyl and
3-guaiazulenyl group and a 1,2-dicyano-4-cyclohexene unit pos-
sessing two substituents at the C-3 and C-6 positions, the signals of
which ware carefully assigned using conventional methodology.
Careful study of the 1H NMR signals suggested a ca. 5:3, mixture of
chromatographically inseparable diastereomers 9a and 9b (see
Experimental section 4.1.6). The 13C NMR spectrum exhibited 25
(for 9a) and 26 (for 9b) carbon signals assigned using HMQC and
HMBC. Thus, the spectroscopic data for 9 led to the molecular
structure illustrated in Scheme 5. A similar reaction pathway to that
of 8 can be inferred for the formation of 9.
Figure 7. The visible spectra of the reaction of 6E (red solid line) with TCNE in benzene
under argon, giving a product 8 (green solid line), selectively. Length of the Cell, 1.0 cm.
Reaction conditions: to a solution of TCNE (0.7 mg, 5.5
mmol) in benzene (1 mL) was
added a solution of 6E (1.0 mg, 2.7
m
mol) in benzene (2 mL) at 25 ꢀC under argon,
2.7. Reaction of 6E with DMAD
turning the green solution of 6E into a blue solution of 8, rapidly.
2.6. Reaction of 6E with DCNE
For comparative purposes, the reaction of 6E with DMAD was
carried out under the same reaction conditions as for the reaction
of 6E with TCNE, the reaction of which gave no product; however,
this reaction in toluene at reflux temperature (110 ꢀC) for two days
under argon afforded a new Diels–Alder adduct 10 in 58% isolated
yield (see Scheme 6), owing to the influence of reaction tempera-
ture. The molecular structure of 10 was established on the basis of
similar spectroscopic analyses to those of 8. In relation to our study,
in 1994 Coudert et al. reported that the reactions of (2E,4E)-1,3-
For comparative purposes, the reaction of 6E with DCNE was
carried out under the same reaction conditions as for the reaction of
6E with TCNE, the reaction of which gave no product. This reaction in
toluene at reflux temperature (110 ꢀC) for four days under argon
afforded a new Diels–Alder adduct 9 very slightly, while the reaction
in p-xylene at reflux temperature (138 ꢀC) for four days under argon
yielded 9 in 54% isolated yield (see Scheme 5), owing tothe influence
of reaction temperature. The molecular structure of 9 was estab-
lished on the basis of similar spectroscopic analyses to those of 8.
Scheme 5. The reaction of 6E with DCNE in p-xylene at reflux temperature (138 ꢀC) for
four days under argon.
Compound 9 was obtained as blue needles. Similar to 8, the
characteristic UV–vis absorption bands of 6E were not observed,
Figure 8. The UV–vis spectrum of
9
in benzene. Concentration, 9:
value is given in parenthesis.
0.10 g Lꢁ1(223
mmol). Length of the Cell, 0.1 cm. Each log
3

S.-i. Takekuma et al. / Tetrahedron 66 (2010) 3004–3015
3011
butadiene derivatives with dimethyl acetylenedicarboxylate at
130–150 ꢀC for 15 min–1 h yielded similar Diels–Alder adducts to
10 in 51–82% isolated yields,39 each partial structure cis-3,6-
substituted 1,2-dimethoxycarbonyl-1,4-cyclohexadiene, estab-
lished on the basis of 1H NMR spectral analysis, of which coincided
with that of 10.
Figure 10. The ORTEP drawing, with a numbering scheme (30% probability thermal
ellipsoids), of 11. The selected bond lengths (Å) of 11 are as follows: C1–C2; 1.384(4),
C2–C3; 1.400(4), C3–C3a; 1.409(4), C3a–C4; 1.413(4), C4–C5; 1.403(5), C5–C6; 1.379(5),
C6–C7; 1.374(6), C7–C8; 1.394(6), C8–C8a; 1.391(4), C8a–C1; 1.411(5), C3a–C8a;
1.498(4), C1–C9; 1.501(4), C4–C10; 1.515(4), C7–C11; 1.510(6), C11–C12; 1.418(7), C11–
C13; 1.475(7), C10–C20; 1.347(4), C20–C30; 1.522(3), C30–C40; 1.505(4), C40–C50; 1.324(4),
C50–C60; 1.520(4), C60–C10; 1.501(4), C10–C70; 1.501(4), C70–O80; 1.203(4), C70–O90;
1.332(3), O90–C100; 1.440(3), C20–C110; 1.499(4), C110–O120; 1.208(3), C110–O130;
1.336(3), O130–C140; 1.445(4), C60–C3; 1.533(3), C30–C100; 1.520(4), C100–C200; 1.391(4),
C200–C300; 1.375(4), C300–C400; 1.390(4), C400–C500; 1.397(4), C500–C600; 1.392(4), C600–C100;
1.389(4), C400–N700; 1.375(4), and N700–C800; 1.425(4).
Scheme 6. The reaction of 6E with DMAD in toluene at reflux temperature (110 ꢀC) for
two days gives 10, which upon oxidation with MnO2 in CH2Cl2 at 25 ꢀC for 1 h affords 11.
then determined by means of X-ray diffraction, producing accurate
structural parameters. The ORTEP drawing with a numbering
scheme is shown in Figure 10, indicating the molecular structure 11
illustrated in Scheme 6. It is found that the methoxycarbonyl group
at the C10 position is upright against the other methoxycarbonyl
group at the C20 position and the distance between the C110 and O80
atoms is 2.57 Å, suggesting the formation of the Cdþ/Odꢁ co-
ordinate bond. Thus, the crystal structure of 11 supported the
molecular structure 10, possessing a partial structure cis-3,6-
substituted 1,2-dimethoxycarbonyl-1,4-cyclohexadiene, illustrated
in Scheme 6.
Compound 10 was obtained as a blue solid. Similar to 8, the
characteristic UV–vis absorption bands of 6E were not observed,
while those based on guaiazulene36 were observed as shown in
Figure 9 and the longest visible absorption wavelength appeared at
lmax 616 nm (log
3
¼2.73). The molecular formula C33H37O4N was
determined by exact FABMS spectrum. The 1H NMR (including
NOE) spectrum showed signals based on a 4-(dimethylamino)-
phenyl and 3-guaiazulenyl group and a cis-3,6-substituted 1,2-
dimethoxycarbonyl-1,4-cyclohexadiene unit, the signals of which
ware carefully assigned using conventional methodology. The 13C
NMR spectrum exhibited 29 carbon signals assigned using HMQC
and HMBC. Thus, the spectroscopic data for 10 led to the molecular
structure illustrated in Scheme 6. A similar reaction pathway to that
of 8 can be inferred for the formation of 10.
3. Conclusion
We have reported the following ten interesting points for the
title basic studies: namely, (i) the Wittig reaction of the aldehyde 5
with the reagent 4 in ethanol containing NaOEt at 25 ꢀC for 24 h
under argon gave the title new (2E,4E)-1,3-butadiene derivative 6E
in 19% isolated yield; (ii) the spectroscopic data of 6E compared
with those of the previously reported (E)-ethylene derivative 12
were documented and further, the longest visible absorption
We have further found that the oxidation of 10 with MnO2 in
CH2Cl2 at 25 ꢀC for 1 h gives 11, converting a (CH3)2N-400 into
CH3NH-400 group, in 37% isolated yield (see Scheme 6). Although it
was very difficult to obtain a single crystal of 10 suitable for X-ray
crystallographic analysis, recrystallization of 11 from a mixed sol-
vent of hexane and ethyl acetate (5:1, vol/vol) provided a single
crystal suitable for that purpose. The crystal structure of 11 was
wavelengths of 6E and 12 corresponded to their Dp-HOMO–p-
LUMO/eV energy levels; (iii) the crystal structure of 6E could be
determined, supporting the molecular structure established on the
basis of spectroscopic data, the accurate structural parameters of
which enabled us to compare with those of 12; (iv) similar to 12, the
electrochemical behavior of 6E showed that it serves as a more
strong two-electron donor in comparison with 12 and a similar
one-electron acceptor to 12 and further, the redox potentials of 6E
and 12 corresponded to their
levels; (v) a redox mechanism based on the redox potentials and
the -HOMO and -LUMO distribution diagrams of 6E compared
p-HOMO and p-LUMO/eV energy
p
p
with those of 12 was proposed; (vi) although the reaction of 6E
with 2 equiv of TCNE in benzene at 25 ꢀC for 24 h under argon did
not give 7 possessing a similar structure to 18–21, the reaction
afforded a new Diels–Alder adduct 8, in 59% isolated yield; (vii)
along with the spectroscopic properties of 8, the crystal structure of
8 could be determined, supporting the 3,6-cis-form established on
the basis of spectroscopic data, and further, a reaction pathway for
Figure 9. The UV–vis spectrum of 10 in benzene. Concentration, 10:
0.18 g Lꢁ1(352
mmol). Length of the Cell, 0.1 cm. Each log 3 value is given in parenthesis.

3012
S.-i. Takekuma et al. / Tetrahedron 66 (2010) 3004–3015
the formation of 8 via Diels–Alder reaction was proposed; (viii) the
reaction of 6E with DCNE under the same reaction conditions as for
the reaction of 6E with TCNE gave no product; however, this re-
action in p-xylene at reflux temperature (138 ꢀC) for four days
under argon afforded a new Diels–Alder adduct 9, in 54% isolated
yield, owing to the influence of reaction temperature; (ix) although
the reaction of 6E with DCNE in toluene at reflux temperature
(110 ꢀC) for four days under argon provided 9 very slightly, the
reaction of 6E with DMAD in toluene at reflux temperature for two
days under argon yielded a new Diels–Alder adduct 10, in 58%
isolated yields, which upon oxidation with MnO2 in CH2Cl2 at 25 ꢀC
for 1 h gave 11, converting a (CH3)2N-400 into CH3NH-400 group, in
37% isolated yield. The crystal structure of 11 supported the mo-
carefully washed with diethyl ether to provide pure 4 as a blue
powder (195 mg, 352 mol, 93% yield).
m
4.1.2. Preparation of (2E,4E)-4-[4-(dimethylamino)phenyl]-1-(3-
guaiazulenyl)-1,3-butadiene (6E). To a solution of commercially
available 3-[4-(dimethylamino)phenyl]propanal (5) (32 mg,
183 mmol) in ethanol (5 mL) was added a solution of (3-guaiazule-
nylmethyl)triphenylphosphonium bromide (4) (100 mg, 181
mmol)
in ethanol (5 mL) containing sodium ethoxide (25 mg, 367
mmol).
The mixture was stirred at 25 ꢀC for 24 h under argon. After the re-
action, distilled-water was added to the mixture, and then the
resulting product was extracted with dichloromethane (20 mLꢂ3).
The extract was washed with distilled-water, dried (MgSO4), and
evaporated in vacuo. The residue thus obtained was carefully sepa-
rated by silica gel column chromatography with hexane/ethyl ace-
lecular structure 10 possessing
a partial structure cis-3,6-
substituted 1,2-dimethoxycarbonyl-1,4-cyclohexadiene; and (x)
a similar reaction pathway to that of 8 could be inferred for the
formation of 9 and 10.
tate (9:1, vol/vol) as an eluant. The crude product
6 was
recrystallized from methanol/chloroform (5:1, vol/vol) (several
times) to provide pure 6E (13 mg, 35 mmol,19% yield) as stable single
crystals.
4. Experimental
4.1. General
Compound 6E: Black plates [Rf¼0.19 on silica gel TLC (solv.
hexane/ethyl acetate¼9:1, vol/vol)]; mp 176 ꢀC; UV–vis lmax/nm
(log 3) in CH2Cl2, 232 (4.33), 265 (4.26), 302 (4.21), 352 (4.48), 431
(4.73), 450sh (4.70), and 659 (2.77); IR nmax/cmꢁ1 (KBr), 2955–2800
(C–H), 2955, 980 (–HC]CH–), 1601, 1520 (C]C), and 1354 (C–N);
exact EIMS (70 eV), found: m/z 369.2477; calcd for C27H31N: Mþ,
m/z 369.2457; 500 MHz 1H NMR (benzene-d6), signals based on
Melting points were taken on a Yanagimoto MP-S3 instrument.
FAB- and EIMS spectra were taken on a JEOL The Tandem Mstation
JMS-700 TKM data system. UV–vis and IR spectra were taken on
a Beckman DU640 spectrophotometer and a Shimadzu FTIR-4200
Grating spectrometer. NMR spectra were recorded with a JEOL
GX-500 (500 MHz for 1H and 125 MHz for 13C) and JNM-ECA700
a 3-guaiazulenyl group:
d
1.19 (6H, d, J¼6.9 Hz, (CH3)2CH-70), 2.523
(3H, br s, Me-10), 2.71 (1H, sept, J¼6.9 Hz, (CH3)2CH-70), 2.81 (3H, s,
Me-40), 6.55 (1H, J¼10.3 Hz, H-50), 6.97 (1H, dd, J¼10.3, 2.0 Hz, H-
60), 7.93 (1H, d, J¼2.0 Hz, H-80), and 7.98 (1H, br s, H-20); signals
(700 MHz for 1H and 176 MHz for C) cryospectrometer at 25 ꢀC.
13
1H NMR spectra were assigned using computer-assisted simulation
(software: gNMR developed by Adept Scientific plc) on a DELL Di-
mension 9150 personal computer with a Pentium IV processor.
Cyclic and differential pulse voltammograms (CV and DPV) were
measured with an ALS Model 600 electrochemical analyzer.
based on a 4-(dimethylamino)phenyl group: d 2.519 (6H, s,
(CH3)2N-400), 6.61 (2H, dd, J¼8.9, 2.4 Hz, H-300,500), and 7.47 (2H, dd,
J¼8.9, 2.4 Hz, H-200,600); and signals based on a (2E,4E)-1,3-butadi-
ene unit:
d
6.77 (1H, d, J¼14.9 Hz, H-4), 7.07 (1H, dd, J¼14.9, 10.5 Hz,
H-2), 7.15 (1H, dd, J¼14.9, 10.5 Hz, H-3), and 7.67 (1H, d, J¼14.9 Hz,
H-1); 125 MHz 13C NMR (benzene-d6), 150.1 (C-400), 146.4 (C-40),
d
4.1.1. Preparation of (3-guaiazulenylmethyl)triphenylphosphonium
141.6 (C-8a0), 140.6 (C-70), 136.4 (C-20), 134.7 (C-60), 133.4 (C-80),
132.8 (C-3a0), 131.2 (C-4), 129.2 (C-2), 128.7 (C-1), 127.7 (C-200,600),
127.5 (C-3), 127.4 (C-100), 127.3 (C-50), 126.5 (C-10), 126.5 (C-30), 113.0
(C-300,500), 40.1 ((CH3)2N-400), 37.9 ((CH3)2CH-70), 28.4 (Me-40), 24.4
((CH3)2CH-70), and 13.1 (Me-10).
bromide
(4). Guaiazulene-3-carbaldehyde (¼5-isopropyl-3,8-
dimethylazulene-1-carbaldehyde) (2), which is a synthetic in-
termediate of the Wittig reagent 4, was prepared according to the
following procedure: namely, to a solution of commercially avail-
able guaiazulene (¼7-isopropyl-1,4-dimethylazulene) (1) (100 mg,
504
m
mol) in N,N-dimethylformamide (DMF) (3 mL) was added
4.1.3. X-ray crystal structure of (2E,4E)-4-[4-(dimethylamino)-
phenyl]-1-(3-guaiazulenyl)-1,3-butadiene (6E). A total 10,197 re-
flections with 2qmax¼55.0ꢀ were collected on a Rigaku AFC-5R
automated four-circle diffractometer with graphite mono-
a solution of phosphoryl chloride (100
mL). The mixture was stirred
at 0 ꢀC for 1 h. After the reaction, the reaction solution was carefully
neutralized with aq KOH and then the resulting product was
extracted with dichloromethane (10 mLꢂ3). The extract was
washed with distilled water, dried (Na2SO4), and evaporated in
vacuo. The residue thus obtained was carefully separated by silica
gel column chromatography with hexane/ethyl acetate (3:2, vol/
vol). The crude product was recrystallized from hexane to provide
chromated Mo K
a
radiation (l¼0.71069 Å, rotating anode: 50 kV,
180 mA) at ꢁ75 ꢀC. The structure was solved by direct methods
(SIR92) and expanded using Fourier techniques (DIRDIF99). 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
performed using the teXsan crystallographic software package.
Crystallographic data have been deposited with Cambridge Crys-
tallographic Data Center: Deposition number CCDC-669534 for
compound No. 6E. 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 Centre, 12, Union Road, Cam-
bridge, CB2 1EZ, UK; Fax: þ44 1223 336033; e-mail:
deposit@ccdc.cam.ac.uk).
pure 2 as stable crystals (108 mg, 477
ously, the Wittig reagent 4 was prepared according to the following
procedure: namely, to a powder of NaBH4 (30 mg, 793 mol) was
added a solution of 2 (90 mg, 397 mol) in ethanol (1.5 mL). The
mmol, 94% yield). Continu-
m
m
mixture was stirred at 25 ꢀC for 1 h. After the reaction, distilled
water (10 mL) was added to the mixture and then the resulting
product was extracted with dichloromethane (10 mLꢂ3). The ex-
tract was washed with distilled water, dried (Na2SO4), and evapo-
rated in vacuo to provide pure 3-guaiazulenylmethanol (3) as a blue
paste, quantitatively. To a solution of the obtained 3 in chloroform
(3 mL) was added a solution of triphenylphosphonium bromide
Crystallographic data for 6E: C27H31N (FW¼369.55), black plate
(crystalsize,1.00ꢂ0.60ꢂ0.30 mm3), triclinic, P-1(#2), a¼14.753(5) Å,
(130 mg, 378
mmol) in chloroform (3 mL). The mixture was refluxed
b¼17.080(5) Å,
c¼9.585(4) Å,
a
¼99.86(3)ꢀ,
b
¼108.74(3)ꢀ,
for 1 h under argon. After cooling, the reaction mixture was poured
into diethyl ether (10 mL), precipitating a blue solid, and then was
centrifuged at 2.5 krpm for 1 min. The obtained product was
g
¼69.46(2)ꢀ, V¼2137.1(13) Å3, Z¼4, Dcalcd¼1.148 g/cm3,
m(Mo
Ka
)¼0.653 cmꢁ1, scan width¼(1.42þ0.30 tan
q
)ꢀ, scan mode¼
uꢁ2q,
scan rate¼16.0ꢀ/min, measured reflections¼10,197, observed

S.-i. Takekuma et al. / Tetrahedron 66 (2010) 3004–3015
3013
reflections¼9817, No. of parameters¼568, R1¼0.0523, wR2¼0.1758,
goodness of fit indicator¼0.983.
four days under argon. After the reaction, the reaction solution was
evaporated in vacuo. The residue thus obtained was carefully sep-
arated by silica gel column chromatography with hexane/ethyl
acetate (3:1, vol/vol) as an eluant. The crude product was recrys-
tallized from hexane/ethyl acetate (5:1, vol/vol) (several times)
to provide pure 3-{1,2-dicyano-3-[4-(dimethylamino)phenyl]-4-
4.1.4. Reaction of (2E,4E)-4-[4-(dimethylamino)phenyl]-1-(3-guaia-
zulenyl)-1,3-butadiene
(6E)
with
1,1,2,2-tetracyanoethylene
(TCNE). To a solution of compound 6E (15 mg, 41
mmol) in benzene
(2 mL) was added a solution of TCNE (10 mg, 78
mmol) in benzene
cyclohexen-6-yl}guaiazulene (9) (10 mg, 22 mmol, 54% yield) as
(2 mL) under argon, turning the green solution of 6E into a blue
solution, rapidly. The mixture was stirred at 25 ꢀC for 24 h under
argon. After the reaction, the reaction solution was evaporated in
vacuo. The crude product thus obtained was recrystallized from
ethyl acetate/hexane (5:1, vol/vol) (several times) to provide pure
3-{1,1,2,2-tetracyano-cis-3-[4-(dimethylamino)phenyl]-4-cyclohexen-
6-yl}guaiazulene (8), with an equivalent of AcOEt molecule, as
stable crystals.
Compound 9: Blue needles [Rf¼0.25 on silica gel TLC (solv. hex-
ane/ethyl acetate¼3:1, vol/vol)]; mp 259 ꢀC; UV–vis lmax/nm (log
3)
in benzene, 295 (4.80), 307sh (4.58), 353 (3.90), 370 (3.87), 609
(2.78), 666sh (2.68), and 738sh (2.21); IR nmax/cmꢁ1 (KBr), 3024–
2808 (C–H), 2245 (C^N), 1612, 1524 (C]C), and 1362 (C–N); exact
FABMS (3-nitrobenzyl alcohol matrix), found: m/z 447.2692; calcd
for C31H33N3: Mþ, m/z 447.2674. The relative intensity of the 1H
NMR signals for the diastereomers 9a and 9b showed a ratio of ca.
5:3.
stable single crystals (14 mg, 24 mmol, 59% yield).
Compound 8: Blue plates [Rf¼0.30 on silica gel TLC (solv. hexane/
ethyl acetate¼3:1, vol/vol)]; mp 223 ꢀC; UV–vis lmax/nm (log
3) in
benzene, 297 (4.70), 309sh (4.62), 356 (3.82), 372 (3.86), 434 (2.59),
453sh (2.57), 592 (2.68), and 647sh (2.54); IR nmax/cmꢁ1 (KBr),
2963–2812 (C–H), 2249 (C^N), 1612, 1528 (C]C), and 1366 (C–N);
exact FABMS (3-nitrobenzyl alcohol matrix), found: m/z 497.2589;
calcd for C33H31N5: Mþ, m/z 497.2579; 700 MHz 1H NMR (benzene-
Compound 9a: 700 MHz 1H NMR (benzene-d6), signals based on
a 3-guaiazulenyl group:
d
1.19 (6H, d, J¼7.0 Hz, (CH3)2CH-7), 2.52
(3H, s, Me-1), 2.78 (1H, sept, J¼7.0 Hz, (CH3)2CH-7), 2.91 (3H, s, Me-
4), 6.83 (1H, d, J¼10.6 Hz, H-5), 7.17 (1H, dd, J¼10.6, 2.2 Hz, H-6),
7.72 (1H, s, H-2), and 8.17 (1H, d, J¼2.2 Hz, H-8); signals based on
d6), signals based on a 3-guaiazulenyl group:
d
1.12 (6H, d, J¼6.9 Hz,
a 4-(dimethylamino)phenyl group: d
2.54 (6H, s, (CH3)2N-400), 6.64
(CH3)2CH-7), 2.53 (3H, s, Me-1), 2.70 (1H, sept, J¼6.9 Hz, (CH3)2CH-
7), 2.93 (3H, s, Me-4), 6.74 (1H, d, J¼10.8 Hz, H-5), 7.12 (1H, dd,
J¼10.8, 2.2 Hz, H-6), 8.05 (1H, br s, H-2), and 8.09 (1H, d, J¼2.2 Hz,
(2H, dd, J¼8.6, 2.5 Hz, H-300,500), and 7.32 (2H, dd, J¼8.6, 2.5 Hz,
H-200,600); and signals based on a 1,2-dicyano-4-cyclohexene unit
possessing two substituents at the C-3 and C-6 positions:
d 2.60
H-8); signals based on a 4-(dimethylamino)phenyl group:
d
2.42
(1H, dd, J¼10.6, 5.8 Hz, H-10), 3.04 (1H, dd, J¼10.6, 9.5 Hz, H-20),
3.37 (1H, dddd, J¼9.5, 2.3, 2.2, 2.2 Hz, H-30), 4.73 (1H, dddd, J¼5.8,
4.2, 2.4, 2.2 Hz, H-60), 5.67 (1H, ddd, J¼9.9, 2.4, 2.2 Hz, H-40), and
5.71 (1H, ddd, J¼9.9, 4.2, 2.4 Hz, H-50); 176 MHz 13C NMR (benzene-
(6H, s, (CH3)2N-400), 6.51 (2H, dd, J¼8.8, 2.6 Hz, H-300,500), and 7.33
(2H, dd, J¼8.8, 2.6 Hz, H-200,600); and signals based on a cis-3,6-
substituted 1,1,2,2-tetracyano-4-cyclohexene unit:
d 4.11 (1H, ddd,
J¼2.8, 2.8, 2.8 Hz, H-30), 5.64 (1H, ddd, J¼10.6, 3.0, 2.8 Hz, H-40),
d6), d
150.6 (C-400), 140.6 (C-4,7), 139.6 (C-8a), 139.4 (C-2), 135.4
5.66 (1H, ddd, J¼3.0, 2.8, 2.8 Hz, H-60), and 5.84 (1H, ddd, J¼10.6,
(C-6), 134.5 (C-8), 134.2 (C-3a), 131.2 (C-40), 129.0 (C-50,200,600), 128.8
(C-5), 125.0 (C-1), 124.6 (C-100), 122.6 (CN), 119.2 (CN), 117.6 (C-3),
113.2 (C-300,500), 44.4 (C-30) 40.0 ((CH3)2N-400), 37.8 ((CH3)2CH-7),
35.9 (C-10), 35.3 (C-60), 34.2 (C-20), 28.5 (Me-4), 24.6 ((CH3)2CH-7),
and 13.2 (Me-1).
3.0, 2.8 Hz, H-50); 176 MHz 13C NMR (benzene-d6),
d
151.4 (C-400),
144.4 (C-4), 142.2 (C-7), 140.7 (C-2), 140.2 (C-8a), 135.6 (C-6), 135.1
(C-8,3a), 131.5 (C-200,600), 130.2 (C-5), 128.3 (C-50), 125.9 (C-40), 125.0
(C-1), 120.1 (C-100), 117.0 (C-3), 113.3, 112.6, 111.0, 110.7 (CN each),
112.2 (C-300,500), 46.6 (C-30), 45.0, 44.7 (C-10,20), 42.7 (C-60), 39.6
((CH3)2N-400), 37.8 ((CH3)2CH-7), 28.1 (Me-4), 24.4 ((CH3)2CH-7),
and 13.0 (Me-1).
Compound 9b: 700 MHz 1H NMR (benzene-d6), signals based on
a 3-guaiazulenyl group:
d
1.22 (6H, d, J¼7.0 Hz, (CH3)2CH-7), 2.52
(3H, s, Me-1), 2.79 (1H, sept, J¼7.0 Hz, (CH3)2CH-7), 2.90 (3H, s, Me-
4), 6.75 (1H, d, J¼10.6 Hz, H-5), 7.15 (1H, dd, J¼10.6, 2.0 Hz, H-6),
7.59 (1H, s, H-2), and 8.14 (1H, d, J¼2.0 Hz, H-8); signals based on
4.1.5. X-ray crystal structure of 3-{1,1,2,2-tetracyano-cis-3-[4-(di-
methylamino)phenyl]-4-cyclohexen-6-yl}guaiazulene (8) with an
equivalent of AcOEt molecule. A total 7779 reflections with
a 4-(dimethylamino)phenyl group:
d
2.54 (6H, s, (CH3)2N-400), 6.64
(2H, dd, J¼8.6, 2.5 Hz, H-300,500), and 7.34 (2H, dd, J¼8.6, 2.5 Hz, H-
2
qmax¼55.0ꢀ were collected on a Rigaku AFC-5R automated four-
200,600); and signals based on a 1,2-dicyano-4-cyclohexene unit
circle diffractometer with graphite monochromated Mo K
tion (
a
radia-
possessing two substituents at the C-3 and C-6 positions: d 2.57
l
¼0.71069 Å, rotating anode: 50 kV, 180 mA) at ꢁ75 ꢀC. The
(1H, dd, J¼11.2, 5.2 Hz, H-20), 3.13 (1H, dd, J¼11.2, 10.0 Hz, H-10),
3.31 (1H, dddd, J¼5.2, 4.8, 2.2, 2.0 Hz, H-30), 4.67 (1H, dddd, J¼10.0,
2.2, 2.2, 2.2 Hz, H-60), 5.37 (1H, ddd, J¼10.0, 4.8, 2.2 Hz, H-40), and
5.67 (1H, ddd, J¼10.0, 2.2, 2.0 Hz, H-50); 176 MHz 13C NMR (ben-
structure was solved by direct methods (SIR97) and expanded using
Fourier techniques (DIRDIF94). Non-hydrogen atoms were refined
anisotropically. Hydrogen atoms were included but not refined. The
finalcycle offull-matrixleast-squaresrefinementwasbased onF2. All
calculations were performed using the teXsan crystallographic soft-
warepackage.DepositionnumberCCDC-669772forcompoundNo.8.
Crystallographic data for 8 with an equivalent of AcOEt molecule:
C37H39O2N5 (FW¼585.75), blue plate (crystal size, 0.50ꢂ0.40ꢂ
0.90 mm3), triclinic, P-1 (#2), a¼14.174(4) Å, b¼15.123(4) Å,
zene-d6),
d
150.7 (C-400), 140.5 (C-4,7), 139.6 (C-8a), 136.9 (C-2),
135.0 (C-6), 134.3 (C-8), 133.2 (C-3a), 130.8 (C-200,600), 128.8 (C-5),
128.3 (C-50), 125.5 (C-40), 125.0 (C-1), 124.5 (C-100), 122.6 (CN), 119.2
(CN), 117.8 (C-3), 112.7 (C-300,500), 40.6 (C-30), 40.2 (C-60), 40.1
((CH3)2N-400), 37.9 ((CH3)2CH-7), 36.3 (C-20), 33.9 (C-10), 28.1 (Me-
4), 24.5 ((CH3)2CH-7), and 13.3 (Me-1).
c¼8.005(5) Å,
a
¼94.53(4)ꢀ,
b
¼100.11(4)ꢀ,
g
¼74.27(2)ꢀ, V¼1625(1) Å3,
Z¼2, Dcalcd¼1.197 g/cm3,
m
(Mo
Ka
)¼0.75 cmꢁ1
,
scan width¼
4.1.7. Reaction of (2E,4E)-4-[4-(dimethylamino)phenyl]-1-(3-guaia-
zulenyl)-1,3-butadiene (6E) with dimethyl acetylenedicarboxylate
(DMAD). To a solution of compound 6E (31 mg, 84
(5 mL) was added a solution of DMAD (40 L, 326
gon. The mixture was stirred at reflux temperature (110 ꢀC) for two
days under argon. After the reaction, the reaction solution was
evaporated in vacuo. The residue thus obtained was carefully sep-
arated by silica gel column chromatography with hexane/ethyl
acetate (2:1, vol/vol) as an eluant. The crude product thus obtained
was recrystallized from hexane/ethyl acetate (5:1, vol/vol) to
(1.37þ0.30 tan
q
)ꢀ, scan mode¼
uꢁ2
q
, scan rate¼14.0ꢀ/min, measured
reflections¼7779, observed reflections¼7476, No. of parameters¼397,
R1¼0.067, wR2¼0.183, goodness of fit indicator¼1.49.
m
mol) in toluene
mmol) under ar-
m
4.1.6. Reaction of (2E,4E)-4-[4-(dimethylamino)phenyl]-1-(3-guaia-
zulenyl)-1,3-butadiene (6E) with (E)-1,2-dicyanoethylene (DCNE). To
a solution of compound 6E (15 mg, 41
added a solution of DCNE (7 mg, 90 mol) in p-xylene (2 mL) under
argon. The mixture was stirred at reflux temperature (138 ꢀC) for
mmol) in p-xylene (2 mL) was
m

3014
S.-i. Takekuma et al. / Tetrahedron 66 (2010) 3004–3015
provide pure 3-{1,2-dimethoxycarbonyl-cis-3-[4-(dimethylami-
no)phenyl]-1,4-cyclohexadiene-6-yl}guaiazulene (10) (25 mg,
X-ray measurement of the single crystal 11 was made on a Rigaku
Saturn CCD area detector with graphite monochromated Mo K
a
49
m
mol, 58% yield) as a solid.
Compound 10: Blue solid [Rf¼0.35 on silica gel TLC (solv. hexane/
) in benzene, 294
radiation (
l
¼0.71075 Å) at ꢁ140ꢃ1 ꢀC. The structure was solved by
direct methods (SIR92) and expanded using Fourier techniques
(DIRDIF99). 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 calcula-
tions were performed using the Crystal Structure crystallographic
software package developed by Rigaku corporation, Japan. De-
position number CCDC-749884 for compound No. 11.
ethyl acetate¼2:1, vol/vol)]; UV–vis lmax/nm (log
3
(4.66), 309sh (4.47), 358 (3.93), 376 (3.91), 616 (2.73), 670sh (2.65),
and 750sh (2.27); exact FABMS (3-nitrobenzyl alcohol matrix),
found: m/z 511.2723; calcd for C33H37O4N: Mþ, m/z 511.2723;
700 MHz 1H NMR (benzene-d6), signals based on a 3-guaiazulenyl
group:
d
1.189, 1.190 (3H each, d, J¼7.0 Hz, (CH3)2CH-7), 2.49 (3H, br
s, Me-1), 2.76 (1H, sept, J¼7.0 Hz, (CH3)2CH-7), 2.93 (3H, br s, Me-4),
6.73 (1H, d, J¼10.6 Hz, H-5), 7.12 (1H, dd, J¼10.6, 2.2 Hz, H-6), 8.08
(1H, d, J¼2.2 Hz, H-8), and 8.08 (1H, br s, H-2); signals based on a 4-
Crystallographic data for 11: C32H35O4N (FW¼497.63), blue
block (the crystal size, 0.64ꢂ0.35ꢂ0.10 mm3), monoclinic, P21/n
(#14), a¼12.444(3) Å, b¼10.355(2) Å, c¼20.602(4) Å,
b
¼93.547(5)ꢀ,
(dimethylamino)phenyl group:
d
2.52 (6H, s, (CH3)2N-400), 6.67 (2H,
V¼2649.7(9) Å3, Z¼4, Dcalcd¼1.247 g/cm3,
m(Mo K
a
)¼0.813 cmꢁ1
,
dd, J¼8.6, 2.5 Hz, H-300,500), and 7.46 (2H, dd, J¼8.6, 2.5 Hz, H-200,600);
measured reflections¼25,169, observed reflections¼3747, No. of
parameters¼370, R1¼0.0674, wR2¼0.1997, goodness of fit
indicator¼0.964.
and signals based on
a cis-3,6-di-substituted 1,2-dimethoxy-
carbonyl-1,4-cyclohexadiene unit:
1 or 2), 4.62 (1H, m, H-30), 5.63, 5.64 (1H each, m, H-50, 60), and 5.84
(1H, m, H-40); 176 MHz 13C NMR (benzene-d6),
168.9, 167.8
d 3.08, 3.40 (3H each, s, H3COOC-
d
Acknowledgements
(H3COOC-10 or 20), 150.1 (C-400), 144.8 (C-4), 139.8 (C-8a), 139.6 (C-
7), 139.4 (C-2), 138.2 (C-20), 134.4 (C-6), 134.3 (C-10), 133.8 (C-8),
131.9 (C-3a), 129.8 (C-200,600), 129.5 (C-100), 127.9 (C-40), 127.2 (C-5),
125.4 (C-1),124.5 (C-50), 113.1 (C-300,500), 51.5, 51.4 (H3COOC-10 or 20),
44.0 (C-30), 40.2 ((CH3)2N-400), 38.2 (C-60), 37.9 ((CH3)2CH-7), 27.4
(Me-4), 24.63, 24.60 ((CH3)2CH-7), and 13.2 (Me-1). The C-3 carbon
signal was included in other signals.
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.
Supplementary data
4.1.8. Oxidation of 3-{1,2-dimethoxycarbonyl-cis-3-[4-(dimethyl-
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2010.02.064.
amino)phenyl]-1,4-cyclohexadiene-6-yl}guaiazulene
(10)
with
MnO2. To solution of compound 10 (25 mg, 49
a
mmol) in
dichloromethane (5 mL) was added a solution of dichloromethane
(5 mL) with MnO2 (10 mg, 115 mol). The mixture was stirred at
References and notes
m
25 ꢀC for 24 h. After the reaction, MnO2 was removed by using
a centrifugal separator and then the reaction solution was evapo-
rated in vacuo. The residue thus obtained was carefully separated
by silica gel column chromatography with hexane/ethyl acetate
(2:1, vol/vol) as an eluant. The crude product thus obtained was
recrystallized from hexane/ethyl acetate (5:1, vol/vol) to provide
pure 3-{1,2-dimethoxycarbonyl-cis-3-[4-(methylamino)phenyl]-
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Compound 11: Blue blocks [Rf¼0.25 on silica gel TLC (solv. hex-
ane/ethyl acetate¼2:1, vol/vol)]; mp 181 ꢀC; exact FABMS
(3-nitrobenzyl alcohol matrix), found: m/z 497.2551; calcd for
C32H35O4N: Mþ, m/z 497.2566; 700 MHz 1H NMR (benzene-d6),
signals based on a 3-guaiazulenyl group:
d 1.190, 1.191 (3H each, d,
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J¼7.0 Hz, (CH3)2CH-7), 2.48 (3H, br s, Me-1), 2.76 (1H, sept,
J¼7.0 Hz, (CH3)2CH-7), 2.92 (3H, br s, Me-4), 6.72 (1H, d, J¼10.6 Hz,
H-5), 7.12 (1H, dd, J¼10.6, 2.0 Hz, H-6), 8.06 (1H, br s, H-2), and 8.08
(1H, d, J¼2.0 Hz, H-8); signals based on a 4-(methylamino)phenyl
group:
d
2.32 (3H, s, CH3NH-400), 6.44 (2H, dd, J¼8.4, 2.3 Hz, H-
300,500), and 7.39 (2H, dd, J¼8.4, 2.3 Hz, H-200,600). The MeNH-400
proton signal was not observed; and signals based on a cis-3,6-di-
substituted
d
1,2-dimethoxycarbonyl-1,4-cyclohexadiene
unit:
3.08, 3.40 (3H each, s, H3COOC-1 or 2), 4.59 (1H, m, H-30), 5.61,
13
5.62 (1H each, m, H-50, 60), and 5.83 (1H, m, H-40); 176 MHz
NMR (benzene-d6),
C
d
169.0, 167.7 (H3COOC-10 or 20), 148.9 (C-400),
144.8 (C-4), 139.7 (C-8a), 139.6 (C-7), 139.4 (C-2), 138.5 (C-20), 134.4
(C-6), 134.1 (C-10), 133.7 (C-8), 131.9 (C-3a), 129.9 (C-200,600), 128.3
(C-40), 127.2 (C-5), 125.3 (C-1), 124.5 (C-50), 112.7 (C-300,500), 51.5, 51.4
(H3COOC-10 or 20), 44.2 (C-30), 38.1 (C-60), 37.9 ((CH3)2CH-7), 30.4
(CH3NH-400), 27.3 (Me-4), 24.62, 24.60 ((CH3)2CH-7), and 13.1 (Me-
1). The C-3 and C-100 carbon signals were included in other signals.
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(methylamino)phenyl]-1,4-cyclohexadiene-6-yl}guaiazulene (11). The
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S.-i. Takekuma et al. / Tetrahedron 66 (2010) 3004–3015
3015
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20), and 8.07 (1H, d, J¼2.0 Hz, H-80); signals based on a 4-(dimethylamino)-
phenyl group:
d
2.44 (6H, s, (CH3)2N-400), 6.43 (2H, dd, J¼8.8, 2.3 Hz, H-300,500),
and 7.33 (2H, dd, J¼8.8, 2.3 Hz, H-200,600); and signals based on a (2Z,4E)-1,3-
butadiene unit:
d
6.59 (1H, ddd, J¼11.2, 10.8, 0.6 Hz, H-2), 6.85 (1H, br d, J¼15.
4 Hz, H-4), 7.21 (1H, br d, J¼10.8 Hz, H-1), and 7.63 (1H, ddd, J¼15.4, 11.2, 1.2 Hz,
H-3).
33. The accurate parameters for the crystal structures of 6EB and 12 were trans-
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36. Guaiazulene (1): UV–vis lmax/nm (log 3) in CH3CN, 213 (4.10), 244 (4.39), 284
´
31. Dumur, F.; Mayer, C. R.; Dumas, E.; Miomandre, F.; Frigoli, M.; Secheresse, F. Org.
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32. (2Z,4E)-4-[4-(Dimethylamino)phenyl]-1-(3-guaiazulenyl)-1,3-butadiene (6Z):
Green paste [Rf¼0.26 on silica gel TLC (solv. hexane/ethyl acetate¼9:1, vol/vol)
under the same conditions as for 6E];500 MHz 1H NMR (benzene-d6), signals
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d
1.20 (6H, d, J¼7.0 Hz, (CH3)2CH-70), 2.54
(3H, br s, Me-10), 2.76 (1H, sept, J¼7.0 Hz, (CH3)2C H-70), 2.86 (3H, s, Me-40),
39. Moreau, P.; Guillaument, G.; Coudert, G. Tetrahedron 1994, 50, 3407–3414.