# An Efficient Preparation, Spectroscopic Properties, and Crystal Structure of 1,1-Bis(4-[2-(dimethylamino)ethoxy]phenyl)-2-(3-guaiazulenyl)ethylene

Authors: Shin-ichi Takekuma; Seiki Hori; Toshie Minematsu; Hideko Takekuma
Journal: Research Letters in Organic Chemistry
 (2009)

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## Abstract

Reaction of 2-(3-guaiazulenyl)-1,1-bis(4-hydroxyphenyl)ethylene with 2-chloroethyldimethylammonium chloride in acetone in the presence ofK2CO3 at reflux temperature for 24 hours gives a new title compound in 89% yield. Spectroscopic properties and crystal structure of the target molecule are reported.


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## Body

## 1. Introduction

It is well known that chlorotrianisene
[2-chloro-1,1,2-tris(4-methoxyphenyl)ethylene]  (1) [1] exhibits significant estrogenic activity, while tamoxifen [(Z)-1-[4-(2-dimethylaminoethoxy)phenyl]-1,2-diphenyl-1-butene]  (2) [1–4] exhibits
significant antiestrogenic activity, owing to the difference between the
substituents of 1 and those of 2 (see
Figure 1). Furthermore, tamoxifen,
which serves as a nonsteroidal antiestrogen [3], has become a widely used drug
for a first-line endocrine therapy for all stages of breast cancer in pre- and
postmenopausal women [5]. On the other hand, azulene, possessing a large dipole
moment, is regarded as one of the representative examples of non-benzenoid
aromatic hydrocarbons, and naturally occurring guaiazulene (7-isopropyl-1,4-dimethylazulene)
(see Figure 1) [6] has been widely used clinically as an anti-inflammatory and
antiulcer agent. However, none have really been used as other industrial materials.
In relation to azulene chemistry, in 2004, we reported that the reaction of
guaiazulene with 1,2-bis(4-methoxyphenyl)-1,2-ethanediol in methanol in the
presence of hydrochloric acid at 60°C for 3 hours gave 2-(3-guaiazulenyl)-1,1-bis(4-methoxyphenyl)ethylene
(5) (see Figure 2), possessing a
similar structure to 1, in 97% yield
[7]. Similarly, the reaction of guaiazulene with 1,2-bis(4-hydroxyphenyl)-1,2-ethanediol under the same reaction conditions as
the above afforded 2-(3-guaiazulenyl)-1,1-bis(4-hydroxyphenyl)ethylene (3) (see Figure 3) in 73% yield [7]. As a
series of basic studies on our azulene chemistry [7–17], our interest
has quite recently been focused on an efficient preparation and properties of new
tamoxifen analogues with a 3-guaiazulenyl (7-isopropyl-1,4-dimethylazulen-3-yl)
group, for example, the title compound 4. We now wish to report a facile preparation as well as the spectroscopic
properties and the crystal structure of the target compound 4 (see Figure 3).Figure 1Figure 2Figure 3
The reaction of3 with 2-chloroethyldimethylammonium
chloride in acetone in the presence of potassium carbonate at reflux temperature for 24 hours.


## 2. Results and Discussions

Compound4 (89% yield) was prepared in acetone,
according to the procedure shown in Figure 3, the molecular structure of which was
established on the basis of elemental analysis and spectroscopic data [UV-vis, IR, exact FAB-MS, and 1H and 13C
NMR including NOE and 2D NMR (i.e., H−H COSY, HMQC, and HMBC)].
1H  NMR signals (δ and J values) were carefully assigned using computer-assisted simulation based on first-order analysis
(1H  NMR signals were assigned using computer-assisted simulation (software: gNMR developed by Adept Scientific plc) on a DELL Dimension XPS T500 personal-computer with a Pentium III processor.).The UV-vis spectrum of4, possessing a 1,1-bis(4-[2-(dimethylamino)ethoxy]phenyl)ethylene
part, compared with that of structurally related π-electron system 5 [7] showed that the spectral pattern of 4 resembled that of 5; however, the longest absorption wavelength of 4 (λmax 632 nm, logε=2.72) revealed a slight hyperchromic
effect (Δlogε=0.18) in comparison with that of 5 (λmax 635 nm, logε=2.54). The IR spectrum showed specific
bands based on the C−O, C−N, aromatic C=C, and C−H bonds. The protonated molecular formula
C37H47O2N2 was determined by exact FAB-MS spectrum. The elemental analysis
confirmed the molecular formula C37H46O2N2.
The 1H  NMR spectrum showed signals based on a 3-guaiazulenyl group,
signals based on two nonequivalent 4-[2-(dimethylamino)ethoxy]phenyl groups,
and a signal based on an ethylene part (>C=CH−). The 13C  NMR spectrum exhibited
29 carbon signals, which could be assigned using HMQC and HMBC techniques.
Thus, the elemental analysis and the spectroscopic data for 4 led to the title molecular structure.The crystal structure of4 was then determined by means of X-ray diffraction. Two molecules
of 4 were found to exist in the unit
cell of the crystal. The ORTEP drawing of 4 (one of the two molecules) with a numbering scheme is shown in Figure 4(a). The
structural parameters of 4 revealed
that the C1−C1′, C1−C1′′, C2−C3′′′, and C1=C2 bond lengths of 4 coincided with those of 5 [7]. Similarly,
as in the case of 5, the aromatic
rings of the two 4′- and 4′′-[2-(dimethylamino)ethoxy]phenyl and 3′′′-guaiazulenyl
groups of 4 twisted by 47.9°, 135.0°,
and 47.4° from the plane of the >C=CH− part, owing to the influence of large steric hindrance and repulsion
between the aromatic rings. The average C−C bond lengths for the seven- and five-membered rings of the 3′′′-guaiazulenyl
group of 4 (1.412 and 1.422Å) coincided
with those of 5 (1.405 and 1.427Å)
and the average C−C bond lengths for the benzene rings of the two 4′- and 4′′-[2-(dimethylamino)ethoxy]phenyl
groups of 4 (1.386 and 1.385Å) also
coincided with those of the two 4′- and 4′′-methoxyphenyl groups of 5 (1.382 and 1.380Å).The ORTEP drawings with the numbering scheme (30% probability thermal ellipsoids) of4 and 1.
(a)(b)Comparing the bond lengths observed for4 to those of 2 [4], it was found that the C1=C2 bond length of 4 coincided with that of 2 (1.34Å)
and the C1−C1′ and C1−C1′′ bond lengths of 4 also coincided
with those of 2 (1.50Å each). The
average C−C bond lengths observed for the 1′- and 1′′-phenyl groups of 4 coincided with those of 2 (1.39Å each), and the bond lengths observed
for the two (dimethylamino)ethoxy groups of 4 also coincided with those of 2 (C4′–O:1.38, O–CH2:1.44, CH2–CH2:1.51, CH2–N:1.50, N–CH3:1.34, and N–CH3:1.26Å). The (dimethylamino)ethoxy
side chain of 2 is essential to the
antiestrogenic action [1]. From the accurate structural parameters of 4, a study on the antiestrogenic
activity of 4, compared with that of 2, is noteworthy.The crystal structure of the estrogenic drug1 was not documented. For comparative
purposes, the crystal structure of 1 (Commercially available 1 was recrystallized from diethyl ether (several times) to provide stable single crystals (mp 114°C).) has been determined by means of X-ray diffraction (Crystallographic data for 1: C23H21O3Cl (FW  =  380.87), colorless prism (the crystal size, 0.50×0.40×0.40mm3), monoclinic, C2/c(#15),a=18.577(5)Å,b=9.787(5)Å,c=23.738(4)Å, β=115.82(1)°,V=3885(2)Å3,Z=8,Dcalcd=1.302g/cm3,μ(MoKα)=2.17cm−1,    scanwidth=(1.26+0.30tanθ)°,scanmode=ω−2θ,scanrate=8.0°/min,   measured reflections  =  4882, observed  reflections  =  4461, No. of parameters  =  244,  R1=0.041,wR2=0.167, and goodness of fit indicator  =  1.35. Deposition           no.  CCDC-252847 for compound no. 1.). The ORTEP drawing
of 1 with a numbering scheme is
shown in Figure 4(b). The structural parameters of 1 revealed that the C1=C2 bond length of 1 coincided with those of (Z)-2-chloro-1-(4-methylphenyl)-1,2-diphenylethylene
(6) [1.340(3)Å]  (see Figure 2) [18], 5 [7], and 4. The C1−C1′, C1−C1′′, and C2−C1′′′ bond lengths of 1 also
coincided with those of 4−6. The benzene rings of the three 4′-, 4′′-, and 4′′′-methoxyphenyl
groups of 1 twisted by 64.4°, 103.5°,
and 41.3° from the plane of the >C=CCl− part, owing to the influence of large steric hindrance and repulsion
between the benzene rings. The average C−C bond lengths for the benzene rings of the 4′-, 4′′-, and
4′′′-methoxyphenyl groups of 1 (1.384
Å each) coincided with those of the 4′- and 4′′-methoxyphenyl groups of 5 and the 4′- and 4′′-[2-(dimethylamino)ethoxy]phenyl
groups of 4. The accurate crystal
structure determination of 1 and 4, along with that of 5, is important from a viewpoint of computational study on
the compounds’ potential interactions with specific residues within the human
estrogen receptor.


## 3. Experimental

Preparation of4
Compound4 was prepared
according to the following procedure. To a solid of anhydrous K2CO3 (17 mg, 123 mmol) was added a solution of 3 (50 mg, 123 mmol) in acetone (10 mL). The mixture was stirred at 25°C
for 12 hours, and then 2-chloroethyldimethylammonium chloride (36 mg, 250 mmol)
was added to the mixture. The mixture was stirred at reflux temperature for 24
hours. After the reaction, distilled water was added to the mixture, and then
the resulting product was extracted with diethyl ether (10 mL  ×  3). The extract
was washed with distilled water, dried (MgSO4), and evaporated in
vacuo. The residue thus obtained was carefully separated by silica-gel column
chromatography with methanol-dichloromethane (3:7,
vol/vol) as an eluant. The crude product was recrystallized from petroleum
ether to provide pure 4 (60 mg, 109 mmol,
89% yield) as stable crystals.Compound4: dark-green needles [Rf  =  0.10 on silica-gel TLC (solv. methanol:dichloromethane  =  1:9, vol/vol)]; mp 100°C [determined by thermal analysis (TGA and
DTA)]; found: C, 80.69; H, 8.41; N, 5.08%; calcd for C37H46O2N2:
C, 80.69; H, 8.42; N, 5.09%; UV-vis λmax (CH3CN) nm (logε), 271 (4.52), 329 (4.40), 357sh (4.30), 409 (4.27), and 632 (2.72); IR
υmax(KBr) cm−1, 2955−2766 (C−H), 1605, 1508 (C=C), 1285 (C−N), and 1242, 1042 (C−O); exact FAB-MS (3-nitorobenzylalcohol matrix), found: m/z 551.3664; calcd for C37H47O2N2:
[M  +  H]+, m/z 551.3638; 500 MHz １H  NMR: (CD3CN), signals based on the 3-guaiazulenyl group: δ1.28 (6H, d, J  =  7.0 Hz, (C H3)2CH-7′′′),
2.38 (3H, s, CH3-1′′′), 2.94 (3H, s, CH3-4′′′), 2.97 (1H,
sept, J  =  7.0 Hz, (CH3)2C H-7′′′), 6.81 (1H, d, J  =  10.5 Hz, H-5′′′), 6.89 (1H, s, H-2′′′), 7.24 (1H, dd, J  =  10.5, 2.5 Hz, H-6′′′), and 7.92 (1H, d, J  =  2.5 Hz, H-8′′′); signals based on the (Z)-4-[2-(dimethylamino)ethoxy]phenyl
group: δ2.22 (6H, s, (CH3)2N),
2.60 (2H, t, J  =  6.0 Hz, CH2–N), 3.98
(2H, t, J  =  6.0 Hz, CH2–O), 6.74
(2H, dd, J  =  8.5, 2.5 Hz, H-3′,5′), and 7.04
(2H, dd, J  =  8.5, 2.5, Hz H-2′,6′); and signals
of based on the (E)-4-[2-(dimethylamino)ethoxy]phenyl
group: δ2.24 (6H, s, (CH3)2N),
2.63 (2H, t, J  =  6.0 Hz, CH2–N), 4.03
(2H, t, J  =  6.0 Hz, CH2–O), 6.84
(2H, dd, J  =  8.5, 2.5 Hz, H-3′′,5′′), and 7.22
(2H, dd, J  =  8.5, 2.5 Hz, H-2′′,6′′); and a
signal based on the >C=CH− part: δ7.52 (1H, s, H-2); 125 MHz
13C  NMR (CD3CN), δ159.3 (C-4′′), 158.9 (C-4′),
147.1 (C-4′′′), 141.5 (C-7′′′), 140.2 (C-2′′′), 139.5 (C-8a′′′), 138.9 (C-1′′),
137.5 (C-1′), 135.7 (C-6′′′), 135.4 (C-3a′′′), 134.4 (C-1), 134.1 (C-8′′′),
133.4 (C-2′,6′), 129.6 (C-2′′,6′′), 127.2 (C-5′′′), 127.1 (C-3′′′), 125.8
(C-2), 125.4 (C-1′′′), 115.1 (C-3′′,5′′), 115.0 (C-3′,5′), 67.2 (CH2–O-4′′),
67.1 (CH2–O-4′), 59.0 (CH2–N′′), 58.9 (CH2–N′),
46.1 (Me2N  ×  2), 38.4 ((CH3)2CH-7′′′), 27.9 (Me-4′′′), 24.6 ((CH3)2CH-7′′′), and
12.9 (Me-1′′′).Crystallographic Data for4
C37H46O2N2  (FW  =  550.78), dark-green prism (the
crystal size, 0.50  ×  0.20  × 0.50 mm3), triclinic, P-1 (#2), a  =  16.904(3)Å, b  =  20.322(4)Å, c  =  10.372(1)Å, α  =  103.00(1)°, β  =  96.90(1)°, γ  =  108.53(1)°, V  =  3220.4(9)Å3, Z  =  4, Dcalcd  =  1.136 g/cm3, μ(Mo Kα)  =  0.69 cm−1, scan width  =  (1.26+0.30tanθ)°,
scan mode  =  ω−2θ, scan rate  =  16.0°/min, measured reflections  =  15303, observed reflections  =  11731, no. of parameters  =  739, R1  =  0.063,
wR2  =  0.177, and goodness of fit indicator  =  1.48. Crystallographic data of 4 have been deposited with Cambridge
Crystallographic Data Center, Deposition no. CCDC-635049 for compound no. 4.
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: +44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk).


## 4. Conclusions

We have reported the following three interesting points in this paper,
namely, (i) the reaction of 2-(3-guaiazulenyl)-1,1-bis(4-hydroxyphenyl)ethylene
(3) with 2-chloroethyldimethylammonium
chloride in acetone in the presence of K2CO3 at reflux
temperature for 24 hours gave a new title compound 4 in 89% yield; (ii) the elemental analysis and the spectroscopic
data for 4 led to the target
molecular structure; (iii) the crystal structure of 4 compared with those of structurally related compounds
2-(3-guaiazulenyl)-1,1-bis(4-methoxyphenyl)ethylene (5), tamoxifen (2), and chlorotrianisene
(1) was documented. From the accurate structural parameters of 4, a comparative study on the antiestrogenic activity of 4 with that of 2 is noteworthy.



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