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. Author manuscript; available in PMC: 2012 Sep 12.
Published in final edited form as: ACS Comb Sci. 2011 Jul 13;13(5):501–510. doi: 10.1021/co200090p

Parallel Synthesis of a Desketoraloxifene Analogue Library via Iodocyclization/Palladium-Catalyzed Coupling

Chul-Hee Cho †, Dai-Il Jung †,‡, Benjamin Neuenswander §, Richard C Larock †,*
PMCID: PMC3171577  NIHMSID: NIHMS309970  PMID: 21721520

Abstract

graphic file with name nihms309970u1.jpg

For a future structure-activity relationship (SAR) study, a library of desketoraloxifene analogues has been prepared by parallel synthesis using iodocyclization and subsequent palladium-catalyzed coupling reactions. Points of desketoraloxifene diversification involve the two phenolic hydroxyl groups and the aliphatic amine side chain. This approach affords oxygen-bearing 3-iodobenzo[b]thiophenes 4 in excellent yields, which are easily further elaborated using a two-step approach involving Suzuki-Miyaura and Mitsunobu coupling reactions to give multimethoxy-substituted desketoraloxifene analogues 6. Various hydroxyl-substituted desketoraloxifene analogues 7 were subsequently generated by demethylation with BBr3.

Keywords: parallel synthesis, desketoraloxifene, iodocyclization, benzo[b]thiophene, selective estrogen receptor modulator (SERM), palladium coupling

INTRODUCTION

Early cancer drug discovery efforts focused on the design of small molecule nonsteroidal estrogen receptor (ER) ligands with antagonist properties against breast and other reproductive tissues.1 The estrogen receptors alpha and beta (ERα and ERβ) are members of a large family of nuclear receptors that regulate gene transcription in response to small molecule binding.2 Due to the validated therapeutic importance of these receptors in diseases, such as osteoporosis and breast cancer, a number of drugs have been developed that target these estrogen receptors.3

Some of the more important estrogen antagonist structures cited in the literature are summarized in Figure 1. Tamoxifen (I)4 is a well-established estrogen antagonist. Traditionally the design of modulators has involved the preparation of triarylethylene analogues of this parent structure. 4-Hydroxytamoxifen (II)5 is an effective antiestrogen for estrogen receptor positive breast tissue. However, hydroxytamoxifen was subsequently discovered to have undesirable estrogenic properties on the endometrium. Several additional selective estrogen receptor modulators (SERMs), including the benzoxepin scaffold (III),6 the 2-phenylspiroindene scaffold (IV),7 ERA-923 (V),6b, 8 nafoxidine (VI),9 and trioxifene (IV)6b, 10 are presently in late stages of clinical trials. Most approaches to SERMs have involved modifications of the nonsteroidal antagonists tamoxifen (I) and raloxifene (VIII). Although the current SERMs have clear advantages over conventional hormone replacement therapy (HRT), they retain some of the disadvantages as well. Clearly, an “ideal SERM” has not yet emerged.

Figure 1.

Figure 1

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Chemical structures of representative synthetic SERMs with A and B rings corresponding to tamoxifen (I) and raloxifene (VIII).

Because more potent and safer chemotherapeutic agents are needed, due to the potential side effects of tamoxifen (I), considerable attention has been paid to the development of less toxic SERMs.11 Benzothiophene derivatives, specifically those with oxygen-bearing substituents at the C-2, C-5 and/or C-6 positions are biologically important compounds. Many of these are known to be medicinally and physiologically active substances. Raloxifene (VIII) is a SERM), which is currently under clinical evaluation for the prevention and treatment of postmenopausal osteoporosis.4b, 12 Another benzothiophene SERM, arzoxifene (IX), is a highly effective agent for the prevention of mammary cancer induced in the rat by the carcinogen nitrosomethylurea and is significantly more potent than raloxifene in this regard.11, 13 Desmethylarzoxifene (DMA) (X), with a 4′-OH group, is an active metabolite of arzoxifene (IX), which has been observed in highly variable steady-state plasma concentrations.11, 13–14

Interestingly, removal of the ketone moiety in raloxifene results in a benzothiophene analogue SERM, desketoraloxifene (Figure 1) (XI), which is more planar and conformationally more similar to 4-hydroxytamoxifen (II). Desketoraloxifene (XI) has been found to be a much stronger activator of the Activator Protein-1 (AP-1) site by ERα than ERβ, and mimics 4-hydroxytamoxifen (II) more than raloxifene (VIII).6b, 12b, 15

The benzo[b]thiophene SERMs VIII–XI have four important structural features, the benzothiophene aromatic ring, two phenolic hydroxyl groups and the basic aliphatic amine side chain, which are primarily responsible for their biological activity (Figure 2).15 Any new methodology suitable for the investigation of structure activity relationships (SAR) of benzothiophene-based SERMs14, 16 must take into account those four key structural features and be aware that many SERMs in clinical use and clinical development are also highly susceptible to oxidative metabolism by electrophilic, redox active quinoids simply because they are based on polyaromatic phenol scaffolds.17

Figure 2.

Figure 2

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Structure of Benzo[b]thiophene SERMs VIII–XI and the key points of diversification introduced in analogues.

In general, benzo[b]thiophenes are of interest because of their frequent appearance in nature and wide range of biological and physiological effects.18 We have recently shown that the electrophilic cyclization of 2-(1-alkynyl)thioanisoles readily prepared by Sonogashira chemistry provides a very mild, high yielding synthesis of benzothiophenes bearing a bromine, iodine, sulfur or selenium group in the 3 position (Scheme 2).19

Scheme 2.

Scheme 2

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Synthesis of 2,3-Disubstituted Benzo[b]thiophenes by Electrophilic Cyclization

This basic strategy appeared particularly useful for the synthesis of desketoraloxifene analogs 6. In this series, we proposed to initially change the substituents at the C-2, C-3, C-5, and C-6 positions of the benzothiophene ring system. This decision was based on the structure of desketoraloxifene (XI), which has a para-substituted phenol at the 2-position, a basic aliphatic amine-containing chain at the 3-position, and an hydroxyl group at the 6-position of the benzothiophene ring system. Herein, we demonstrate the efficient preparation of oxygen-functionalized 3-iodobenzo[b]thiophenes 4 by electrophilic cyclization using I2 and their further elaboration to desketoraloxifene 7 analogues by solution-phase parallel synthesis.

RESULTS AND DISCUSSION

Using our previously developed benzothiophene methodology, we envisioned an efficient strategy that would lead to a library of methoxy- and hydroxy-substituted desketoraloxifene analogues 6/7 with multiple points of diversity present in the benzothiophene SERM desketoraloxifene analogues. Our basic strategy for generating a large number of such analogues is outlined in Scheme 1. Retrosynthetically, we planned to utilize the oxygen-bearing 3-iodobenzo[b]thiophene derivatives 4 as key intermediates that can be efficiently prepared using our alkyne iodocyclization chemistry.

Scheme 1.

Scheme 1

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Retrosynthetic Route to Fully Substituted Desketoraloxifene Analogues

The requisite precursors 2/3, bearing appropriate oxygen substituents and an alkyne moiety, can be easily prepared by palladium/copper-catalyzed Sonogashira coupling, according to a reported method (1.0 equiv of 1, 1.1 equiv of terminal alkyne, 2 mol % of PdCl2(PPh3)2, 2 mol % of CuI, and Et3N as the solvent at 50 °C for 5–8 h).19b As can be seen from the results reported in Table 1, using the sequence of reactions shown, involving the Sonogashira coupling of compounds 1, and subsequent lithiation of compounds 2{5–15}, followed by methylthiolation with dimethyl disulfide, afforded the corresponding sulfide products 3{1–11} in good to excellent yields.

Table 1.

Sequential Preparation of Alkynes 2{1–15} and 3{1–11} from Aryl Halides 1

graphic file with name nihms309970u2.jpg
entry R1 R2 R3 X alkyne 2 yield (%)a alkyne 3 yield (%)a
1 H H H SMe 2{1} 88
2 H H 4-MeO SMe 2{2} 88
3 H H 3-MeO SMe 2{3} 77
4 H H 2-MeO SMe 2{4} 79
5 MeO H 4-MeO Br 2{5} 94 3{1} 86
6 MeO H 3-MeO Br 2{6} 91 3{2} 93
7 MeO H 2-MeO Br 2{7} 87 3{3} 89
8 MeO H 3,5-(MeO)2 Br 2{8} 83 3{4} 83
9 H MeO 4-MeO Br 2{9} 73 3{5} 81
10 H MeO 2-MeO Br 2{10} 77 3{6} 90
11 MeO MeO 4-MeO Br 2{11} 92 3{7} 87
12 MeO MeO 3-MeO Br 2{12} 79 3{8} 63
13 MeO MeO 2-MeO Br 2{13} 71 3{9} 91
14 OCH2O 4-MeO Br 2{14} 84b 3{10} 73
15 OCH2O 2-MeO Br 2{15} 83b 3{11} 63
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a

Isolated yields after column chromatography.

Our first goal was the efficient preparation of a variety of oxygen-bearing 3-iodobenzothiophenes 4. Those 3-iodobenzo[b]thiophenes 4 have been smoothly prepared in excellent yields by electrophilic cyclization of the corresponding methylthio-containing alkynes 2{1–4} and 3{1–11} using I2 in CH2Cl2 at room temperature for 30 min (Scheme 3 and Figure 3). The chemoselectivity of this reaction is also quite interesting. In examples where MeS and MeO groups are both present ortho to the alkyne, only the desired 3-iodobenzo[b]thiophenes 4 were produced rapidly in high yields (Scheme 4, Figure 3; 4{4,7,10,13,15}).20 None of the possible 3-iodobenzofuran products were observed. In fact, most of the crude 3-iodobenzo[b]thiophenes 4 were of sufficient purity (>95%) for immediate further use based on their clean 1H NMR spectra. All of the reactions were monitored by thin layer chromatography and the products purified by column chromatography (see the Supporting Information for the experimental details).

Scheme 3.

Scheme 3

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Synthesis of Oxygen-Bearing 3-Iodobenzo[b]thiophenes 4 from 2{1–4}/3 by Iodocyclization

Figure 3.

Figure 3

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Synthesis of the oxygen-bearing 3-iodobenzo[b]thiophenes 4{1–15}

Scheme 4.

Scheme 4

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Competition between MeO- and MeS Group

The 3-iodobenzo[b]thiophenes 4, having oxygen substituents at the C-5 and/or C-6 benzothiophene positions, are promising desketoraloxifene analogs (6/7). These 3-iodobenzo[b]thiophenes 4 are easily elaborated using a two-step approach involving Suzuki-Miyaura and subsequent Mitsunobu coupling reactions to give desketoraloxifene analogs 6. Thus, the palladium-catalyzed Suzuki-Miyaura coupling of 3-iodobenzo[b]thiophenes 4 with the tetrahydropyranyl (THP) ether-protected boronic acid p-THPOC6H4B(OH)2, followed by aqueous HCl deprotection, afforded the desired phenolic products 5 in good yields (Scheme 5, see the Supporting Information).19b Unfortunately, we could not obtain the desired compound 5 when we used 4-hydroxyphenylboronic acid directly.

Scheme 5.

Scheme 5

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Suzuki-Miyaura Coupling to Form Phenolic Benzothiophenes 5

For second-generation diversity, various amine-coupled SERM precursors have been produced by reaction of the phenolic benzothiophenes 5 with four different alkylaminoethanol moieties, specifically 1-(2-hydroxyethyl)piperidine, 1-(2-hydroxyethyl)morpholine, 1-(2-hydroxyethyl)pyrrolidine and 2-(dimethylamino)ethanol under Mitsunobu reaction conditions21 using Ph3P and diethyl azodicarboxylate (DEAD) for 24–36 h at room temperature to afford multimethoxy-substituted desketoraloxifene analogues 6 in good yields. The desketoraloxifene analogues 6 allow a wide variety of diversity to be incorporated into the final products. The methoxy-substituted desketoraloxifene analogues 6 have been demethylated using BBr316f to provide the hydroxy-substituted desketoraloxifene analogues 7. These processes have been performed in parallel on approximately a 40–50 mg scale, starting from the methoxy-substituted desketoraloxifene analogues 6. Each coupling reaction was worked up by washing with saturated aqueous sodium bicarbonate, water, and brine, and then the crude products were extracted with 5% methanol in chloroform. Concentration of the organic layer delivered each targeted compound in a modest yield and good purity. Overall, only nine compounds (products 7{10}, 7{11}, 7{16}, 7{20}, 7{34}, 7{35}, 7{36}, 7{38} and 7{39}) failed to afford the anticipated desketoraloxifene analogues by preparative HPLC, primarily because of poor solubility. All of the crude products 7 were isolated by either column chromatography or preparative HPLC. The results of the synthesis of the desketoraloxifene analog library are summarized in Table 2.

Table 2.

Desketoraloxifene Analog Librarya

graphic file with name nihms309970u3.jpg
product 6/7 R1 R2 R3 NR4R5 ion HRMS HRMS (calcd) HRMS (found) purity (%)e yield (%)f
6{1} H H H piperidino [M+H]+ 413.1813 414.1894 98 83
6{2} H H H morpholino [M+H]+ 415.1606 416.1682 >99 78
6{3} H H H pyrrolidino [M+H]+ 399.1657 400.1732 92 81h
6{4} H H H NMe2 [M+H]+ 373.1500 374.1576 98 79
6{5} H H 4-MeO piperidino [M+H]+ 443.1919 444.1987 98 83
7{1}b H H 4-OH piperidino [M+H]+ 429.1762 430.1835 98 27g
6{6} H H 4-MeO morpholino [M+H]+ 445.1712 446.1788 >99 73
7{2}b H H 4-OH morpholino [M+H]+ 431.1555 432.1636 75 23g
6{7} H H 4-MeO pyrrolidino [M]+ 429.1762 429.1765 85
7{3}b H H 4-OH pyrrolidino [M+H]+ 415.1606 416.1681 74 46g
6{8} H H 4-MeO NMe2 [M+H]+ 403.1606 404.1673 98 81
7{4}b H H 4-OH NMe2 [M+H]+ 389.1449 390.1528 70 56
6{9} H H 3-MeO piperidino [M]+ 443.1919 443.1916 78
7{5}b H H 3-OH piperidino [M+H]+ 429.1763 430.1843 >99 53g
6{10} H H 3-MeO morpholino 73
7{6}b H H 3-OH morpholino [M+H]+ 431.1555 432.1636 >99 47
6{11} H H 3-MeO pyrrolidino 76
7{7}b H H 3-OH pyrrolidino [M+H]+ 415.1606 416.1682 98 35g
6{12} H H 3-MeO NMe2 69
7{8}b H H 3-OH NMe2 [M+H]+ 389.1450 390.1525 >99 51g
6{13} H H 2-MeO piperidino [M]+ 443.1919 443.1917 76
7{9}b H H 2-OH piperidino [M+H]+ 429.1763 430.1841 92 17g
6{14} H H 2-MeO morpholino 78
7{10}b H H 2-OH morpholino ndi
6{15} H H 2-MeO pyrrolidino 67
7{11}b H H 2-OH pyrrolidino ndi
6{16} H H 2-MeO NMe2 71
7{12}b H H 2-OH NMe2 [M+H]+ 389.1450 390.1525 >99 12g
6{17} MeO H 4-MeO piperidino [M+H]+ 473.2025 474.2050 99 87
7{13}c OH H 4-OH piperidino [M+H]+ 445.1712 446.1787 99 38g
6{18} MeO H 4-MeO morpholino 74h
7{14}c OH H 4-OH morpholino [M+H]+ 447.1504 448.1579 87 56g
6{19} MeO H 4-MeO pyrrolidino [M]+ 429.1762 429.1768 81
7{15}c OH H 4-OH pyrrolidino [M+H]+ 431.1555 432.1638 86 16g
6{20} MeO H 4-MeO NMe2 81
7{16}c OH H 4-OH NMe2 ndi
6{21} MeO H 3-MeO piperidino [M]+ 473.2025 473.2031 86
7{17}c OH H 3-OH piperidino [M+H]+ 445.1712 446.1790 94 48g
6{22} MeO H 3-MeO morpholino [M+H]+ 475.1817 476.1890 97 83h
6{23} MeO H 3-MeO pyrrolidino 71
6{24} MeO H 3-MeO NMe2 [M+H]+ 433.1712 434.1790 96 82
7{18}c OH H 3-OH NMe2 [M+H]+ 405.1399 406.1475 89 17g
6{25} MeO H 2-MeO piperidino [M+H]+ 473.2025 474.2095 99 87
7{19}c OH H 2-OH piperidino [M+H]+ 445.1712 446.1787 95 52
6{26} MeO H 2-MeO morpholino 81h
6{27} MeO H 2-MeO pyrrolidino [M+H]+ 459.1868 460.1946 98 83
7{20}c OH H 2-OH pyrrolidino ndi
6{28} MeO H 2-MeO NMe2 [M]+ 433.1712 433.1720 83
7{21}c OH H 2-OH NMe2 [M+H]+ 405.1399 406.1475 93 42g
6{29} MeO H 3,5-(MeO)2 piperidino [M]+ 503.2130 503.2132 77
7{22}d OH H 3,5-(OH)2 piperidino [M+H]+ 461.1661 462.1737 33 7g
6{30} MeO H 3,5-(MeO)2 morpholino 78
6{31} MeO H 3,5-(MeO)2 pyrrolidino 73
6{32} MeO H 3,5-(MeO)2 NMe2 73
7{23}d OH H 3,5-(OH)2 NMe2 [M+H]+ 421.1348 422.1362 82 21g
6{33} H MeO 4-MeO piperidino [M+H]+ 473.2025 474.2105 98 83
7{24}c H OH 4-OH piperidino [M+H]+ 445.1712 446.1793 97 78
6{34} H MeO 4-MeO morpholino 78
7{25}c H OH 4-OH morpholino [M+H]+ 447.1504 448.1585 55 43g
6{35} H MeO 4-MeO pyrrolidino 75
7{26}c H OH 4-OH pyrrolidino [M+H]+ 431.1555 432.1633 13 38g
6{36} H MeO 4-MeO NMe2 76
7{27}c H OH 4-OH NMe2 [M+H]+ 405.1399 406.1471 30 47
6{37} H MeO 2-MeO piperidino [M]+ 473.2025 473.2019 78
7{28}c H OH 2-OH piperidino [M+H]+ 445.1712 446.1914 97 37g
6{38} H MeO 2-MeO morpholino 77
7{29} H OH 2-OH morpholino [M+H]+ 447.1504 448.1712 97 49g
6{39} H MeO 2-MeO pyrrolidino 81
7{30}c H OH 2-OH pyrrolidino [M+H]+ 431.1555 432.1703 92 35g
6{40} H MeO 2-MeO NMe2 82
7{31}c H OH 2-OH NMe2 [M+H]+ 405.1399 406.1538 99 31g
6{41} MeO MeO 4-MeO piperidino [M+H]+ 503.2130 504.2146 95 76
7{32}d OH OH 4-OH piperidino [M+H]+ 461.1661 462.1732 >99 12g
6{42} MeO MeO 4-MeO morpholino 75h
7{33}d OH OH 4-OH morpholino [M+H]+ 463.1453 464.1471 97 53g
6{43} MeO MeO 4-MeO pyrrolidino [M]+ 489.1974 489.1981 79
7{34}d OH OH 4-OH pyrrolidino ndi
6{44} MeO MeO 4-MeO NMe2 69
7{35}d OH OH 4-OH NMe2 ndi
6{45} MeO MeO 3-MeO piperidino [M]+ 503.2130 503.2134 79
7{36}d OH OH 3-OH piperidino ndi
6{46} MeO MeO 3-MeO morpholino 81h
6{47} MeO MeO 3-MeO pyrrolidino [M]+ 489.1974 489.1982 73
6{48} MeO MeO 3-MeO NMe2 [M]+ 463.1817 463.1826 72
6{49} MeO MeO 2-MeO piperidino [M+H]+ 503.2130 504.2209 99 77
6{50} MeO MeO 2-MeO morpholino 72
7{37}d OH OH 2-OH morpholino [M+H]+ 463.1453 464.1527 >99 17g
6{51} MeO MeO 2-MeO pyrrolidino 68
7{38}d OH OH 2-OH pyrrolidino ndi
6{52} MeO MeO 2-MeO NMe2 71
7{39}d OH OH 2-OH NMe2 ndi
6{53} OCH2O 4-MeO piperidino [M]+ 487.1817 487.1817 81
6{54} OCH2O 4-MeO morpholino [M+H]+ 489.1610 490.1692 >99 77h
6{55} OCH2O 4-MeO pyrrolidino [M+H]+ 473.1661 474.1754 98 69
6{56} OCH2O 4-MeO NMe2 79
6{57} OCH2O 2-MeO piperidino [M+H]+ 487.1817 488.1896 93 76
6{58} OCH2O 2-MeO morpholino 63h
6{59} OCH2O 2-MeO pyrrolidino 69h
6{60} OCH2O 2-MeO NMe2 [M]+ 447.1504 447.1512 76
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a

Reagents and conditions: i. Mitsunobu Coupling: 5 (0.2 mmol), alkylaminoethanol (1.5 equiv), DIAD (1.5 equiv), PPh3 (2.0 equiv), THF (2.0 mL), rt, 24–36 h. ii. Demethylation: 6 (0.1mmol), BBr3, CH2Cl2 (1.0 mL), rt, N2, 3 h.

b

2.0 Equiv of BBr3 used.

c

4.0 Equiv of BBr3 used.

d

6.0 Equiv of BBr3 used.

e

UV purity determined at 214 nm after preparative HPLC.

f

Isolated yields after column chromatography. All isolated products were characterized by 1H and13C NMR spectroscopy (see the Supporting Information).

g

Isolated yield after preparative HPLC.

h

An inseparable mixture was obtained.

i

The final product was not purified, because of poor solubility.

Desketoraloxifene (XI) itself is an extremely useful compound for biological screening. The dimethoxy-substituted desketoraloxifene analog 6{33} was readily prepared from phenolic benzothiophene 5{9} using 1-(2-hydroxyethyl)piperidine under Mitsunobu coupling conditions. Compound 6{33} was then readily converted by demethylation using BBr3 to desketoraloxifene (XI) in 78% yield (Scheme 6).

Scheme 6.

Scheme 6

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Demethylation to Form Desketoraloxifene (XI)

In conclusion, a total synthesis of desketoraloxifene (XI) and numerous analogues 6/7 have been accomplished from simple alkynes bearing electron-rich aromatic rings by electrophilic cyclization using I2. An efficient synthesis of the key oxygen-bearing intermediate 3-iodobenzo[b]thiophenes 4 has been successfully carried out in good to excellent yields by iodocyclization using I2. For the synthesis of benzothiophene SERMs, the desketoraloxifene analogues 6/7 have been prepared starting from various oxygen-bearing 3-iodobenzo[b]thiophenes 4 by a two-step approach involving sequential Suzuki-Miyaura and Mitsunobu couplings. The benzothiophene SERM desketoraloxifene analog 6/7 library is presently being evaluated against various biological screens by the National Institutes of Health Molecular Library Screening Center Network. We believe that this approach to oxygen-bearing 3-iodobenzo[b]thiophenes 4 should readily afford many other functionalized desketoraloxifene analogues 6 using known chemistry and parallel synthesis strategies.

Experimental Section

General Procedure for the Regioselective Sonogashira Reaction to Form Compounds 2

To a solution of dihalobenzene (1) (10.0 mmol), 2 mol % PdCl2(PPh3)2 and 2 mol % CuI in Et3N (20 mL), the terminal alkyne (11.0 mmol) was added. The reaction mixture was stirred vigorous at 50 °C for 5–8 h under an Ar atmosphere. The resulting mixture was diluted with EtOAc (2 × 200 mL). The separated organic layer was washed with water and brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using ethyl acetate/hexanes as the eluent to afford the corresponding products 2.

4-Bromo-3-[(4-methoxyphenyl)ethynyl]anisole [2{5}]

The product was obtained as a yellow oil (94% yield): 1H NMR (400 MHz, CDCl3) δ 3.76 (s, 3H), 3.80 (s, 3H), 6.71 (dd, J = 3.1, 8.9 Hz, 1H), 6.87 (d, J = 8.9 Hz, 2H), 7.05 (d, J = 3.1 Hz, 1H), 7.44 (d, J = 8.9 Hz, 1H), 7.51 (d, J = 8.9 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 55.5, 55.7, 87.1, 94.0, 114.2 (×2), 115.0, 116.2, 116.3, 117.6, 126.3, 133.1, 133.4 (×2), 158.6, 160.1.; HRMS calcd for C16H13BrO2 [M+], 316.0099, found 316.0094.

General Procedure for Methylthiolation to Form Compounds 3

Bromoalkyne 2 (8.0 mmol) was dissolved in dry THF (80 mL) under an Ar atmosphere and cooled to −78 °C for 0.5 h. Then, n-BuLi (2.0 M solution in cyclohexane, 12.0 mmol) was added dropwise to the stirred solution. After the addition was complete, the reaction solution was stirred for an additional 1 h at −78 °C. Dimethyl disulfide (9.6 mmol) was then added and the reaction mixture was stirred further at this temperature before being allowed to warm to room temperature for 2 h under an Ar atmosphere. The resulting mixture was diluted with EtOAc (2 × 160 mL). The separated organic layer was washed with water and brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using ethyl acetate/hexanes as the eluent to afford the corresponding products 3.

4-Methoxy-2-[(4-methoxyphenyl)ethynyl]thioanisole [3{1}]

The product was obtained as a colorless oil (86% yield): 1H NMR (400 MHz, CDCl3) δ 2.46 (s, 3H), 3.76 (s, 3H), 3.76 (s, 3H), 6.83 (dd, J = 2.8, 8.7 Hz, 1H), 6.86 (d, J = 9.0 Hz, 2H), 7.04 (d, J = 2.8 Hz, 1H), 7.14 (d, J = 8.7 Hz, 1H), 7.51 (d, J = 9.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 16.5, 55.4, 55.5, 86.1, 95.4, 114.1 (×2), 115.2, 115.5, 117.1, 123.9, 127.8, 131.9, 133.2 (×2), 157.3, 159.9; HRMS calcd for C17H16O2S [M+], 284.0871, found 284.0873.

General Procedure for Iodocyclization Using I2 to Form Compounds 4

To a solution of 5.0 mmol of the alkyne 10 and 20 mL of CH2Cl2 was added gradually 1.2 equiv of I2 dissolved in 30 mL of CH2Cl2. The reaction mixture was allowed to stir at room temperature for up to 10 min. The reaction was monitored by TLC to establish completion. The remaining I2 was removed by washing with satd aq Na2S2O3. The mixture was then extracted by EtOAc (2 × 100 mL). The combined organic layers were dried over anhydrous MgSO4 and concentrated under a vacuum to yield the crude product, which was purified by flash chromatography using EtOAc/hexanes as the eluent to afford the corresponding products 4.

3-Iodo-5-methoxy-2-(4-methoxyphenyl)benzo[B]thiophene [4{5}]

The product was obtained as a pale yellow solid (94% yield): mp 114–115 °C (uncorrected); 1H NMR (400 MHz, CDCl3) δ 3.83 (s, 3H), 3.90 (s, 3H), 6.95–7.00 (m, 3H), 7.24 (d, J = 2.4 Hz, 1H), 7.58–7.60 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 55.5, 55.8, 78.8, 108.4, 114.0 (×2), 115.7, 123.0, 127.1, 131.1 (×2), 131.3, 143.2, 143.5, 158.6, 160.2; HRMS calcd for C16H13IO2S[M+], 395.9681, found 395.9684.

General Procedure for Suzuki-Miyaura Coupling to Form Compounds 5

To a solution of 3-iodobenzo[b]thiophene 4 (1.0 mmol) and 5 mol % Pd(PPh3)4 in toluene (10 mL) was added K2CO3 (2.5 mmol) under an Ar atmosphere. To the resulting mixture was added p-(THPO)C6H4B(OH)2 (1.5 mmol) dissolved in ethanol (2 mL) and water (0.5 mL) and the reaction mixture heated to 80 °C for 6–8 h with vigorous stirring. After concentration of the solvent under reduced pressure, 10% aq HCl was added to the crude product in THF (0.1 M conc.) at room temperature and stirred for 1 h. The mixture was then extracted by EtOAc (2 × 20 mL), and the aqueous phase was also extracted with EtOAc or CH2Cl2. The combined organic layers were dried over anhydrous MgSO4 and concentrated under a vacuum to yield the crude product, which was purified by flash chromatography using EtOAc/hexanes as the eluent to afford the corresponding product 5.

3-(4-Hydroxyphenyl)-5-methoxy-2-(4-methoxyphenyl)benzo[B]thiophene [5{5}]

The product was obtained as a pale yellow oil (89% yield): 1H NMR (400 MHz, CDCl3) δ 3.78 (s, 3H), 3.78 (s, 3H), 5.12 (br s, 1H), 6.78 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.5 Hz, 2H), 6.96–7.03 (m, 2H), 7.20 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 8.8 Hz, 2H), 7.70 (d, J = 8.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 55.5, 55.8, 105.8,114.0 (×2), 114.3, 115.9 (×2), 122.9, 127.1, 128.3, 130.8 (×2), 131.1, 131.85 (×2), 131.89, 140.7, 142.4, 155.0, 157.8, 159.2; HRMS calcd for C22H18O3S [M+], 362.0977, found 362.0983.

General Procedure for the Mitsunobu Reaction to Form Compounds 6

To a solution of 5 (0.2 mmol), triphenylphosphine (PPh3) (0.4 mmol), and alkylaminoethanol (0.3 mmol) in anhydrous THF (2 mL) was added diisopropylazodicarboxylate (DIAD) (0.3 mmol) with stirring at 0–5 °C. The resulting solution was stirred at room temperature for 24–32 h (monitored by TLC until completion) and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using methanol/ethyl acetate/hexanes as the eluent to afford the corresponding products 6.

5-Methoxy-2-(4-methoxyphenyl)-3-{4-[2-(1-piperidinyl)ethoxy]phenyl}benzo[B]thiophene [6{17}]

The product was obtained as a pale yellow oil (89% yield): 1H NMR (400 MHz, CDCl3) δ 1.41–1.50 (m, 2H), 1.59–1.66 (m, 4H), 2.50–2.58 (m, 4H), 2.81 (t, J = 6.0 Hz, 2H), 3.779 (s, 3H), 3.780 (s, 3H), 4.15 (t, J = 6.0 Hz, 2H), 6.78 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 6.95–7.03 (m, 2H), 7.20–7.27 (m, 4H), 7.70 (d, J = 8.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 24.4, 26.2 (×2), 55.3 (×2), 55.4, 55.8, 58.3, 66.1, 105.7, 114.0 (×2), 114.4, 115.0 (×2), 122.9, 127.1, 128.2, 130.8 (×2), 131.0, 131.6 (×2), 132.0, 140.6, 142.4, 157.8, 158.2, 159.2; HRMS calcd for C29H32NO3S [M+H+], 474.2103, found 474.2050.

General Procedure for Demethylation to Compounds 7

To a solution of 6 (0.10 mmol) in anhydrous CH2Cl2 (2 mL) cooled in an ice water bath under N2 was added BBr3 (1.0 M solution in CH2Cl2; 4.0 equiv) while stirring. The solution turned orange in color. This solution was stirred for 3 h after slowly warming to room temperature. The reaction was quenched with satd aq NaHCO3 (2 × 2 mL) and the product was extracted with 5% CH3OH/CHCl3 (3 × 5 mL). The combined organic layers were dried over anhydrous MgSO4 and concentrated under a vacuum to yield the crude product, which was purified by column chromatography using 5–10% CH3OH/CHCl3 as the eluent to provide the desketoraloxifene analogues 7.

Desketoraloxifene [7{24}, XI]

The product was obtained as a white solid (68% yield): 1H NMR (400 MHz, DMSO-d6) δ 1.34–1.43 (m, 2H), 1.48–1.57 (m, 4H), 2.50–2.53 (m, 4H), 2.70–2.76 (m, 2H), 4.10 (t, J = 5.7 Hz, 2H), 6.67 (d, J = 8.7 Hz, 2H), 6.84 (dd, J = 2.2, 8.7 Hz, 1H), 6.99 (d, J = 8.7 Hz, 2H), 7.05 (d, J = 8.7 Hz, 2H), 7.17 (d, J = 8.7 Hz, 2H), 7.23 (d, J = 8.7 Hz, 1H), 7.28 (d, J = 2.2 Hz, 1H), 9.62 (s, 1H), 9.65 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 23.7, 25.3 (×2), 54.3 (×2), 57.2, 65.3, 107.0, 114.6, 114.7 (×2), 115.3 (×2), 123.2, 124.6, 127.4, 130.1 (×2), 130.7, 131.0 (×2), 133.5, 134.8, 138.8, 155.1, 156.9, 157.6; HRMS calcd for C27H27NO3S [M+H+], 446.1790, found 446.1793.

Supplementary Material

1_si_001

Acknowledgments

We thank Johnson Matthey, Inc. and Kawaken Fine Chemicals Co. Ltd. for donations of palladium catalysts, and Frontier Scientific and Synthonix for donations of boronic acids.

Funding Sources

Financial support of this work was provided by the National Institute of General Medical Sciences (GM070620 and GM079593) and the National Institutes of Health Kansas University Chemical Methodologies and Library Development Center of Excellence (GM069663).

Footnotes

Supporting Information. Synthetic methods, spectral assignments and copies of 1H and 13C NMR spectra for all previously unreported starting materials and products. This material is available free of charge via the Internet at http://pubs.acs.org.

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Supplementary Materials

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