Hindawi Publishing Corporation
Research Letters in Organic Chemistry
Volume 2009 (2009), Article ID 684359
doi:10.1155/2009/684359

Research Letter

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

Shin-ichi Takekuma,¹ Seiki Hori,¹ Toshie Minematsu,² and Hideko Takekuma¹

¹Department of Applied Chemistry, Faculty of Science and Engineering, Kinki University, 3-4-1 Kowakae, Higashi-Osaka-shi, Osaka 577-8502, Japan
²School of Pharmaceutical Sciences, Kinki University, 3-4-1 Kowakae, Higashi-Osaka-shi, Osaka 577-8502, Japan

Correspondence should be addressed to Shin-ichi Takekuma, takekuma@apch.kindai.ac.jp

Received 24 November 2008; Accepted 20 February 2009

Recommended by William Ogilvie

Reaction of 2-(3-guaiazulenyl)-1,1-bis(4-hydroxyphenyl)ethylene with 2-chloroethyldimethylammonium chloride in acetone in the presence of 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.

Copyright © 2009 Shin-ichi Takekuma et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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 1

Figure 2

Figure 3: The reaction of 3 with 2-chloroethyldimethylammonium chloride in acetone in the presence of potassium carbonate at reflux temperature for 24 hours.

2. Results and Discussions

Compound 4 (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 of 4, possessing a 1,1-bis(4-[2-(dimethylamino)ethoxy]phenyl)ethylene part, compared with that of structurally related -electron system 5 [7] showed that the spectral pattern of 4 resembled that of 5; however, the longest absorption wavelength of 4 ( 632 nm, ) revealed a slight hyperchromic effect () in comparison with that of 5 ( 635 nm, ). 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 of 4 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 1.422) coincided with those of 5 (1.405 and 1.427) 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 1.385) also coincided with those of the two 4′- and 4′′-methoxyphenyl groups of 5 (1.382 and 1.380).

(a)

(b)

Figure 4: The ORTEP drawings with the numbering scheme (30% probability thermal ellipsoids) of 4 and 1.

Comparing the bond lengths observed for 4 to those of 2 [4], it was found that the C1=C2 bond length of 4 coincided with that of 2 (1.34) and the C1−C1′ and C1−C1′′ bond lengths of 4 also coincided with those of 2 (1.50 each). The average C−C bond lengths observed for the 1′- and 1′′-phenyl groups of 4 coincided with those of 2 (1.39 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–CH₃:1.26). 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 drug 1 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, ), monoclinic, , measured reflections  =  4882, observed  reflections  =  4461, No. of parameters  =  244,   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)]  (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 of 4

Compound 4 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.

Compound 4: 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 (CH₃CN) nm (), 271 (4.52), 329 (4.40), 357sh (4.30), 409 (4.27), and 632 (2.72); IR (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 H  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 for 4

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) b  =  20.322(4) c  =  10.372(1) α  =  103.00(1)°, β  =  96.90(1)°, γ  =  108.53(1)°, V  =  3220.4(9)³, Z  =  4, Dcalcd  =  1.136 g/cm³, μ(Mo Kα)  =  0.69 cm⁻¹, scan width  =  ()°, scan mode  =  , 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.

Acknowledgment

This work was partially supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology, Japan.

References

V. C. Jordan, J. M. Schafer, A. S. Levenson, et al., “Molecular classification of estrogens,” Cancer Research, vol. 61, no. 18, pp. 6619–6623, 2001.

V. Lubczyk, H. Bachmann, and R. Gust, “Investigations on estrogen receptor binding. The estrogenic, antiestrogenic, and cytotoxic properties of C2-alkyl-substituted 1,1-bis(4-hydroxyphenyl)-2-phenylethenes,” Journal of Medicinal Chemistry, vol. 45, no. 24, pp. 5358–5364, 2002.

M. J. Meegan, R. B. Hughes, D. G. Lloyd, D. C. Williams, and D. M. Zisterer, “Flexible estrogen receptor modulators: design, synthesis, and antagonistic effects in human MCF-7 breast cancer cells,” Journal of Medicinal Chemistry, vol. 44, no. 7, pp. 1072–1084, 2001.

G. Precigoux, C. Courseille, S. Geoffre, and M. Hospital, “[-(diméthylamino-2 éthoxy)phényl]-1 trans-diphényl-1,2 butène-1 (tamoxfène) (ICI-46474),” Acta Crystallographica Section B, vol. 35, part 12, pp. 3070–3072, 1979.

L. J. Lerner and V. C. Jordan, “Development of antiestrogens and their use in breast cancer: eighth cain memorial award lecture,” Cancer Research, vol. 50, no. 14, pp. 4177–4189, 1990.

Y. Matsubara, H. Yamamoto, and T. Nozoe, “Oxidation products of guaiazulene and other azulenic hydrocarbons,” in Studies in Natural Products Chemistry, Atta-Ur-Rahman, Ed., vol. 14 of Stereoselective Synthesis (Part I), pp. 313–354, Elsevier, Amsterdam, The Netherlands, 1994.

M. Nakatsuji, Y. Hata, T. Fujihara, et al., “Reactions of azulenes with 1,2-diaryl-1,2-ethanediols in methanol in the presence of hydrochloric acid: comparative studies on products, crystal structures, and spectroscopic and electrochemical properties,” Tetrahedron, vol. 60, no. 28, pp. 5983–6000, 2004.

S. Takekuma, Y. Hata, T. Nishimoto, et al., “Reactions of guaiazulene with methyl terephthalaldehydate and 2-hydroxy- and 4-hydroxybenzaldehydes in methanol in the presence of hexafluorophosphoric acid: comparative studies on molecular structures and spectroscopic, chemical and electrochemical properties of monocarbocations stabilized by 3-guaiazulenyl and phenyl groups,” Tetrahedron, vol. 61, no. 28, pp. 6892–6907, 2005.

S. Takekuma, K. Takahashi, A. Sakaguchi, et al., “Reactions of guaiazulene with 2-furaldehyde, thiophene-2-carbaldehyde and pyrrole-2-carbaldehyde in methanol in the presence of hexafluorophosphoric acid: comparative studies on molecular structures and spectroscopic, chemical and electrochemical properties of monocarbocations stabilized by 3-guaiazulenyl and 2-furyl (or 2-thienyl or 2-pyrrolyl) groups,” Tetrahedron, vol. 61, no. 43, pp. 10349–10362, 2005.

S. Takekuma, K. Takahashi, A. Sakaguchi, M. Sasaki, T. Minematsu, and H. Takekuma, “Reactions of (1,2)-1,2-di(2-furyl)-1,2-di(3-guaiazulenyl)ethane and (1,2)-1,2-di(3-guaiazulenyl)-1,2-di(2-thienyl)ethane with tetracyanoethylene (TCNE) in benzene: comparative studies on the products and their spectroscopic properties,” Tetrahedron, vol. 62, no. 7, pp. 1520–1526, 2006.

S. Takekuma, M. Hirosawa, S. Morishita, M. Sasaki, T. Minematsu, and H. Takekuma, “Reactions of ()-1,2-di(3-guaiazulenyl)ethylene and 2-(3-guaiazulenyl)-1,1-bis(4-methoxyphenyl)ethylene with tetracyanoethylene (TCNE) in benzene: comparative studies on the products and their spectroscopic properties,” Tetrahedron, vol. 62, no. 15, pp. 3732–3738, 2006.

S. Takekuma, K. Sonoda, C. Fukuhara, and T. Minematsu, “Reaction of guaiazulene with o-formylbenzoic acid in diethyl ether (or methanol) in the presence of hexafluorophosphoric acid: comparative studies on and NMR spectral properties of 3-guaiazulenylmethylium- and 3-guaiazulenium-ion structures,” Tetrahedron, vol. 63, no. 11, pp. 2472–2481, 2007.

S. Takekuma, K. Tone, M. Sasaki, T. Minematsu, and H. Takekuma, “Reactions of guaiazulene with thiophene-2,5-dicarbaldehyde and furan-2,5-dicarbaldehyde in methanol in the presence of hexafluorophosphoric acid: a facile preparation and properties of delocalized dicarbenium-ion compounds stabilized by two 3-guaiazulenyl groups and a thiophene (or furan) ring,” Tetrahedron, vol. 63, no. 11, pp. 2490–2502, 2007.

S. Takekuma, K. Mizutani, K. Inoue, et al., “Reactions of azulene and guaiazulene with all-trans-retinal and trans-cinnamaldehyde: comparative studies on spectroscopic, chemical, and electrochemical properties of monocarbenium-ions stabilized by expanded -electron systems with an azulenyl or 3-guaiazulenyl group,” Tetrahedron, vol. 63, no. 18, pp. 3882–3893, 2007.

S. Takekuma, M. Tamura, T. Minematsu, and H. Takekuma, “An efficient preparation, crystal structures, and properties of monocarbenium-ion compounds stabilized by 3-guaiazulenyl and anisyl groups,” Tetrahedron, vol. 63, no. 48, pp. 12058–12070, 2007.

S. Takekuma, K. Sonoda, T. Minematsu, and H. Takekuma, “An efficient preparation and spectroscopic and electrochemical properties of quinodimethane derivatives with four 3-(methoxycarbonyl)azulen-1-yl groups,” Tetrahedron, vol. 64, no. 17, pp. 3802–3812, 2008.

S. Takekuma, S. Hori, T. Minematsu, and H. Takekuma, “Preparation, crystal structures, and properties of new conjugated -electron systems with 3-guaiazulenyl and 4-(dimethylamino)phenyl groups,” Bulletin of the Chemical Society of Japan, vol. 81, no. 11, pp. 1472–1484, 2008.

C. Muthiah, K. P. Kumar, S. Kumaraswamy, and K. C. Kumara Swamy, “An easy access to trisubstituted vinyl chlorides and improved synthesis of chloro/bromostilbenes,” Tetrahedron, vol. 54, no. 47, pp. 14315–14326, 1998.