University of Groningen
Carbon-carbon bond formations using organolithium reagents
Heijnen, Dorus
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Chapter 8 : The Cross-Coupling of Carbolithiated Acetylenes and the
Synthesis of Z-Tamoxifen
The direct carbolithiation-cross coupling procedure of diphenylacetylenes is presented in
this chapter. Employing a new palladium nanoparticle based catalyst described in chapter 7,
we were able to couple an alkenyllithium reagent with near perfect E/Z selectivity and good
yield to afford breast cancer drug Z-Tamoxifen in just 2 steps from commercially available
starting materials and with excellent atom economy and reaction mass efficiency. A
comparison to previous synthetic methods is also presented.
8.1 Introduction
The continuous improvement of synthetic routes towards societally relevant materials and/or biologically active compounds has drawn the attention of synthetic chemists for decades.1 In order to reduce waste and increase yields and cost efficiency or to simplify the procedure to prepare the relevant structure, transition metal catalysis has made a large contribution to the field.2 Since the emergence of the Suzuki (B), Stille (Sn) and Negishi (Zn) reactions, the trend in cross coupling methodology,3 has been to transmetallate highly polar (but straightforward to synthesize)
organometallic reagents (RMgX, , RLi) to softer nucleophiles, in order to gain stability, functional group tolerance and reduce the overall sensitivity of the reaction. Major drawbacks of these additional synthetic steps, are longer reaction times, the production of stoichiometric (toxic) waste, and a decrease in cost efficiency.4 Nonetheless, the direct coupling of organometallic reagents arising from a deprotonation or umpolung reaction, has shown great advances in recent years.5 Since these reagents have an intrinsic higher reactivity, the corresponding cross coupling reactions generally take less time, and can be performed at significantly lower temperatures albeit with some compromises regarding functional group tolerance.4 In an attempt to expand the synthetic application of our recently4,5 reported organolithium cross coupling reactions, we envisioned the direct carbolithation-cross coupling to be an important alternative. The carbolithiation of (diphenyl)acetylenes is well-studied, and has led to several useful applications in the field of synthetic organic chemistry.6-10 The quenching of the formed sp2 anion with an electrophile is a direct approach to substituted diarylalkenes (stilbenes). Transmetallation to magnesium, boron, zinc or even aluminum yields an active cross coupling partner, but drastically lowers atom economy and the E-factor.11,12 The direct cross coupling of the formed vinyl organolithium reagent is therefore a highly desired synthetic shortcut, but remains unreported to the best of our knowledge
8.2 Atom economy, reaction mass efficiency and E-factor
For industrial relevant processes, the amount of generated waste is one of the crucial parameters in determining the best synthetic route. There are several ways of expressing the relationship between desired product and waste products,11,12a,b each having their own advantages and flaws. A Williamson ether synthesis reaction is chosen to show the differences between the 3 methods.13 As can be seen in Scheme 8.1, the atom economy12 merely gives the amount of mass of the reactants that theoretically ends up in the product, disregarding yield, stoichiometry and additives or solvents. With the product having a mass of 128, and the combined starting materials 256, an atom economy of 50 % is achieved. Since even on a laboratory scale, the yields in a multi-step synthesis are crucial, the reaction mass efficieny (RME) is a much more usefull way of describing a (multi step) synthesis. Taking also the stoichiometry of the reagents into account, the same reaction only reaches 29 % for the RME. Where the atom economy and RME disregard solvents, catalysts and substances that are used for the purification, the E factor incorporates all of these in the equation and is an attempt at truly describing the relationship between all reagents used and the final (clean) product.11 For clarity, purification has been omitted in this example, yielding an E factor for the ether synthesis of 12 (1/0.084)
Scheme 8.1 Calculation of atom economy, RME and E-factor
For industrial purposes, the E-factor is the method that gives the most detailed picture of a reaction, and it can be further elaborated with weighing factors for each reagent based on their toxicity, yielding a EQ-Factor.11b Finally, the selectivity of a reaction also indicates the amount of side products that is generated, and thus complicates the purification of the desired product. The EQ factor and the quantification of the purification are outside the scope of this work.
8.3 Goal
Trisubstituted alkenes, and triphenylethylenes in particular make up a class of highly potent and valuable drugs with (potential) application in the treatment of a variety of conditions, including (breast) cancer, dyspareunia and osteoporosis.14 Structural variations are found in the substituents on the alkyl-ether substituent (mostly consisting of an amine), para phenylene functionalization, as well as in the alkyl fragment on the remaining alkene position (Figure 8.1).
Figure 8.1 Examples of members of the triphenylethylene family
Current syntheses
Because of its societal value, a plethora of syntheses have been described for Z-Tamoxifen (Scheme 8.2).15-37 McMurry coupling of two ketones is a well-established method for the synthesis of
(hindered) alkenes, and as such has proven capable of constructing the alkene fragment in Tamoxifen with reagents 4 and 6. Alternatively, 1,2-addition to ketone 4 with Grignard reagent 5, followed by elimination yields the alkene, however, it is common that both isomers (E/Z) are isolated via this approach. The transmetallation of lithium intermediate 1 that is the product of carbolithation of the corresponding acetylene, yields the alkenyl-boronic acid/ester (3, M=B), or organozinc reagents (3, M=Zn). The coupling of these reagents with bromide 2 provides a viable route towards the final drug. The transmetallation, however, generates extra synthetic steps and/or stoichiometric waste. It is therefore that a direct coupling of the alkenyllithium reagent 1 that is obtained upon carbolithiation would be preferred.
Scheme 8.2 Synthetic approaches to Z-Tamoxifen
8.4 Optimization synthesis of Tamoxifen
In order to optimize the sequential synthetic steps, the carbolithation of acetylene 7 was performed separately, and after quenching with MeI, subjected to GCMS analysis (Table 8.1). With near perfect selectivity for the Z alkene for all solvents and solvent mixtures, we were hoping to avoid the use of THF (Table 8.1, entry 2) due to expected difficulties for the cross coupling step. However, toluene/TMEDA mixtures (entry 1) or other ethers (entry 3 to 5) did not prove equally efficient as reaction medium compared to THF due to a lower extend of lithiation (70%), and an increased amount of the E-alkene. Attempts to minimize waste production by neat carbolithiation (using only the solvent of the commercially available n-BuLi) resulted in only starting material (entry 6). Reducing the amount of THF by mixing with toluene resulted in incomplete conversion (entry 7). Despite attempts to omit THF as the solvent, we found significantly better results for the carbolithiation in its presence, and therefore decided to use it as the solvent for further optimization. The aim for a synthesis with a high atom-economy/E-factor made the 30% lower conversion of 2-MeTHF a significant drawback.
Table 8.1 Carbolithiation optimization
Entry Solvent 60 min Conv.a 120 min Conv.a Selectivitya/b
1 Toluene/TMEDA(1eq) 32% 32% 75% 2 THF 91% 91% 96% 3 2-Methyl-THF 52% 70% 99% 4 MTBE 0% 6% - 5 Ether 0% 4% - 6 Neat 0% 0% - 7 Toluene/THF 3:1 48% 65% 96%
a) As determined by GC-MS analysis after MeI quench b) E/Z selectivity
Having established the optimized conditions for the carbolithiations (Table 8.1, entry 2), the cross coupling with 1-bromonaphthalene provided the test reaction in the pursuit for the best catalyst. The oxygen activated palladium nanoparticle catalyst described in chapter 7 proved to be very active in the coupling of the two reagents (Table 8.2, entry 1), being only slightly outperformed by the commercial Pd-PEPPSI-Ipent complex (entry 4).
Table 8.2 Catalyst optimization
entry Cat. (5%) Conversion to 8a 1 Pd(PtBu3)2 + O2 82% 2 Pd-dppf - 3 Ni-dppp - 4 PEPPSI-IPent 88% 5 Ni-NHC 51% a) As determined by GC-MS analysis
Nickel and palladium bisphosphines (Pd-dppf and Ni-dppp) gave no conversion to the desired product (entry 2 and 3), but the nickel complex Ni-NHC as described in chapter 6 did provide the triphenylethylene target 8 (entry 5) albeit with lower conversion.
Having tested a small variety of catalysts for the one pot cross coupling with 1-bromonaphthalene, we set out to synthesize the desired pharmaceutical Tamoxifen by means of a direct carbolithiatiocross coupling strategy. Changing the nucleophile for the acetylene carbolithiation from n-butyllithium to ethyllithium gave identical results after a slightly longer reaction time. We were pleased to see that the oxygenated Pd(PtBu3)2 catalyst gave Tamoxifen in a slightly lower yield than
with the naphthalene test substrate, but with good E/Z selectivity (table 8.3, entry 1). Pursuing a cheaper catalyst with a more earth abundant metal center the attempted nickel catalyst gave only small amounts of the desired product (entry 2).
Table 8.3 Catalyst screening : Synthesis of Tamoxifen
Entry Cat. (5%) NMR Yielda
1 Pd(PtBu3)2 + O2 50-65% 2 Ni-NHC 17% 3 PEPPSI-IPent 0% 4 Pd2dba3/Xphos 36% 5 C1b 60% 6 C2b 59%
Reaction conditions : 2 eq. of alkenyllithium reagent was added over 20 min to a stirred solution of arylbromide and (preoxidized) catalyst in toluene at 35°C.Yield determined by 1H-NMR with
1,1,2,2-tetrachloroethane as internal standard. b) 2.5 mol% of the dimer was used
Much to our surprise, our “working horse” catalyst Pd-PEPPSI Ipent5 was completely inactive with bromophenyl-aminoether electrophile 2 (entry 3), whereas it was the most active catalyst with the bromonaphthalene electrophile. The chelating effect of the amino-ether moiety might play a role in this, functioning as a ligand and overcrowding the palladium center thus hampering its reactivity. Other palladium phosphine complexes that have recently shown to be active in related cross coupling reactions were also tested,5 and were found to have very similar reactivity compared to the phosphine pre-catalyst used in entry 1. Being the cheapest of the three related structures (entry 1, 5 and 6), we decided to continue with the initial catalyst of choice. The results of further optimization studies are shown in table 8.4. Varying the temperature did not lead to increased yield (entry 1 and 2) providing the temperature was kept above 30 °C below which no conversion was observed. In an
C1: X = Br C2: X = I
attempt to break up potential vinyllithium aggregates, and activate the organolithium reagent, TMEDA was added, but this resulted in a scharp decline in yield (entry 3). The excess of organolithium reagent could be lowered to 1.3 equivalents without significant loss in yield (entry 4). Further lowering of the catalyst loading (2.5 mol%) led to an inactive system, with no product formed (entry 6 and 7). This complete deactiviation of the catalyst at 2.5 mol% has not been observed before, and is attributed to the strong chelating effect of the aminoether moiety that is present in the substrate. An attempt to prevent the chelating effect of the aminoether side chain to the palladium center by means of the addition of BF3 or MgCl2 did not prove beneficial for the
reaction (entry 8 and 9) . To increase the E factor, and minimize waste caused by solvent, the reaction was performed in a minimal amount of solvent, at a 1 M concentration which led to a slight decrease in yield (entry 10).
Table 8.4 Optimization of carbolithiation-cross-coupling sequence.
Entry Deviation from standard Yielda
1 Temp 50°C 60 2 Temp 35°C 68 3 TMEDA (1 eq.) 25 4 1.3 eq alkenyllithium 65 5 5 % cat., 1.3 eq alkenyl 65 6 2.5 % cat. - 7 2.5 % cat.b - 8 BF3 - 9 MgCl2 58 10 Concentrated (1 M)c 54
Reaction conditions : 2 eq. of alkenyllithium reagent was added over 20 min to a stirred solution of arylbromide and (preoxidized) catalyst in toluene at room temperature. a) Yield determined by 1H-NMR with 1,1,2,2-tetrachloroethane as internal standard. b) Different batch of catalyst c) Initial concentration of aryl-bromide.
Having a setup that produces this pharmaceutical compound in good yield and with minimal waste production (LiBr being the only stoichiometric waste in the last step), we compared our setup with other (recent) reported syntheses of Z-Tamoxifen in the light of atom economy and E-factor. A full overview of the calculated atom economy of various synthetic routes is given in the experimental section. Figure 8.2 shows a large range in atom economy (shown in blue) between different reported syntheses of Tamoxifen. The method described by Hayashi in 2015 is closest to the route described in
this chapter in terms of atom economy, but with an overall yield of the Z-Tamoxifen of 41% scores much lower on RME (shown in red).
Figure 8.2 Atom economy and RME per Tamoxifen synthesis
With our current setup, employing commercially available starting materials, a total atom economy of 0.54 is achieved, and the RME is almost twice than that of the runner-up. The QE factor (taking toxicity and other impacting sources into account) scores even higher, since LiBr, NaCl and HCl are the only stoichiometrically produced waste sources, and the reaction can be performed at slightly elevated temperature in a minimal amount of solvent.
Purification
To establish the optimal isolation method, the synthesized Tamoxifen was purified by means of crystallization, extraction, column chromatography and distillation. The excess (protonated after quenching) organolithium reagent and formed lithiumbromide pose no difficulty in the separation from the product (Figure 8.3). Acid-base extraction or column chromatography are both suitable means to achieve purification.
Figure 8.3 Z-Tamoxifen and side products
The remaining impurity mainly consists of dehalogenated starting material 2-H, as well as 10% of the E-Tamoxifen which exhibit near identical behavior compared to the product in most standard
0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%
Reaction mass efficiency Atom economy
purification techniques. Flash chromatography with an array of different solvents was not able to significantly improve the purity of the Z-Tamoxifen, and would also drastically lower the E factor. Distillation under reduced pressure proved promising, but due to the reaction scale and reaction setup also failed to provide the clean product. Finally, RP-Preperative HPLC in water/acetonitrile yielded the clean product. Though detrimental for the scale up process and E-factor, we believe that the isolation of Z-Tamoxifen on a larger scale is easily perfomed by means of distillation under reduced pressure.
One pot procedure and alternative electrophile coupling.
In chapter 7 the cross coupling with free phenol electrophiles, that led to the corresponding cross coupled phenol derivatives was shown. In order to reduce the step count of this synthetic route, we envisioned the one pot procedure with the free 4-bromophenol, followed by electrophilic quenching with an amino-alkyl-chloride (scheme 8.3) of reaction intermediate 9. Unfortunately, the deprotonation/cross coupling of 4-bromophenol strategy did not lead to significant product formation, and upon MeI quench showed methylated alkenyllithium reagent 1-Me, as well as products arising from lithium halogen exchange.
Scheme 8.3 Attempted one pot synthesis of Tamoxifen
In order to increase the atom economy even further, and omit the need for a heavy halogen coupling partner, the electrophile 2 was also substituted by the lighter, less waste producing corresponding chloride (2-Cl) or methyl ether (2-OMe)(Scheme 8.3).
Pd-PEPPSI complexes have previously shown to be very reactive in the coupling or aryl chlorides with organolithium reagents. Similarly, the Ni-NHC catalysts described in chapter 6 showed cross coupling with aryl ethers and aryillithium reagents. Unfortunately, the combination of the Pd/Cl and Ni/OMedid not give any observable product formation.
8.5 Conclusions and outlook
The carbolithiation of diphenylacetylene, and the consecutive cross coupling with the appropriate 4-bromo-dimethylamine-ethyl-ether(2) yields Z-Tamoxifen with good E/Z selectivity, and with (NMR) yields ranging from 50-65 %. A fraction of the reaction mixture was purified by RP-Prep-HPLC to obtain the pure product, but large scale isolation is yet to be optimized. The method distinguishes itself from previously reported syntheses by its high atom economy, non-toxic waste production, step count and ease of reaction setup. We envision that the final product can be isolated without the need for any column chromatography, by a simple acid-base extraction followed by vacuum distillation. This method showed promising on small scale, but due to scale limitations was replaced by Prep-HPLC. Further optimization could lead to a lowering of the catalyst loading and suppressing the lithium halogen exchange, that leads to the undesired dehalogenated electrophile 2-H, and increasing the E/Z selectivity even further. The organolithium cross coupling platform has proven to be a particularly powerfull strategy for the coupling of less reactive electrophiles (chlorides, fluorides and ethers). Though no results have been achieved with these reagents yet, they would greatly enhance the method, and it would therefore validate further efforts towards this goal.
8.6 References
1) a) B. M. Rosen, K. W. Quasdorf, D. A. Wilson, N. Zhang, A.Resmerita, N. K. Garg, and V. Percec, Chem. Rev. 2011, 111, 1346–1416, b) L. Guo, C.Hsiao, H.Yue, X. Liu, M. Rueping, ACS Catal. 2016, 6, 4438−4442, M. Tobisu, T. Takahira, T. Morioka, N. Chatani J. Am. Chem. Soc. 2016, 138, 6711−6714. b) see chapter 9 c) Total Synthesis of Natural Products, At the Frontiers of Organic Chemistry, L. J. Jack, E.J. Corey, ISBN 978-3-642-34065-9, Springer, Berlin Heidelberg
2) U. V. Mentzel, D. Tanner, J. E. Tønder J. Org. Chem. 2006, 71, 5807-5810, Metal‐Catalyzed Cross‐ Coupling Reactions, F. Diederich, P. J. Stang, Wiley‐VCH Verlag GmbH, Weinheim, Online ISBN: 9783527612222 |DOI:10.1002/9783527612222.
3) E. Negishi, Angew. Chem. Int. Ed. 2011, 50, 6738 – 6764
4) Hornillos, V.; Pinxterhuis, E. B.; Giannerini, M.; Feringa B.L. Nat. Commun. 2016, DOI: 10.1038/ncomms11698
5) M. Busch, M. D. Wodrich, C. Corminboeuf, ACS Catal., 2017, 7 (9), pp 5643–5653 b)
V.Hornillos, M. Giannerini, C.Vila, M. Fañanás-Mastral, B. L. Feringa Org. Lett. 2013 15, 19, 5114-5117. L. M. Castelló, V. Hornillos, C. Vila, M. Giannerini, M. Fañanás-Mastral, B. L. Feringa Org. Lett., 2015, 17 (1), pp 62–65. c) J. Buter, D. Heijnen, C. Vila, V. Hornillos, E. Otten, M. Giannerini, A. J. Minnaard, and B. L. Feringa. Angew. Chem. Int. Ed. 2016, 55, 3620 –3624. d) Hornillos, V.;
Pinxterhuis, E. B.; Giannerini, M.; Feringa B.L. Nat. Commun. 2016, DOI: 10.1038/ncomms11698 6) McKinley, N. F.; O’Shea, D. F. J. Org. Chem. 2006, 71, 9552–9555.
7) Fressigné, C.; Girard, A. L.; Durandetti, M.; Maddaluno, J. Angew. Chem. Int. Ed. 2008, 47, 891– 893.
8) Wu, G.; Cederbaum, F. E.; Negish, E. Tetrahedron Lett. 1990, 31, 493–496.
9) Fressigné, C.; Lhermet, R.; Girard, A. L.; Durandetti, M.; Maddaluno, J. J. Org. Chem. 2013, 78, 9659–9669.
10) Shirakawa, E.; Ikeda, D.; Ozawa, T.; Watanabe, S.; Hayashi, T. Chem. Commun. 2009, 1885–1887. 11) Sheldon, R. a. Chem. Commun,. 2008, 3352–3365. b) http://www.sheldon.nl/roger/efactor.html 12) a) Trost, B. M. Angew. Chem. Int. Ed. 1995, 34, 259–281. b) Green Chemistry Metrics, A.P. Dicks, A. Hent, 2015, Green Chemistry for Sustainability,Springer, DOI 10.1007/978-3-319-10500-0_2 13) https://www.name-reaction.com/williamson-ether-synthesis
14) Medicinal Chemistry of Anticancer Drugs 2015. Carmen Avendano J. Carlos Menendez, Elsevier Science eBook ISBN: 9780444626677 Paperback ISBN: 9780444626493
15) Itami, K.; Kamei, T.; Yoshida, J. I. J. Am. Chem. Soc. 2003, 125, 14670–14671.
16) Tessier, P. E.; Penwell, A. J.; Souza, F. E. S.; Fallis, A. G. Org. Lett. 2003, 5, 2989–2992. 17) Pandey, R.; Wakharkar, R.; Kumar, P. Synth. Commun. 2005, 35, 2795–2800.
18) Cahiez, G.; Moyeux, A.; Poizat, M. Chem. Commun. 2014, 50, 8982.
19) Murray, P. R. D.; Browne, D. L.; Pastre, J. C.; Butters, C.; Guthrie, D.; Ley, S. V. Org. Process Res. Dev. 2013, 17, 1192–1208.
20) Stiidemann, T.; Knochel, P. Angew. Chem. Int. Ed. 1997, 36, 93–95. 21) Coe, P. L.; Scriven, C. E. J. Chem. Soc. Perkin Trans, 1986, 475–477. 22) Miller, R. B.; Al-hassan, M. I. J. Org. Chem 1985, 58, 2121–2123. 23) Brown, S. D.; Armstrong, R. W. J. Org. Chem. 1997, 62, 7076–7077.
24) Crombie, L.; Jones, R. C. F.; Palmer, C. J. J. Org. Chem, 1982, 47, 2387–2393. 25) Aitken, J. Tetrahedron Lett. 1995, 36, 221–224.
26) Stiidemann, T.; Knochel, P. Angew. Chem. Int. Ed. 1997, 63 93–95. 27) Matsumoto, K.; Shindo, M. Adv. Synth. Catal. 2012, 354, 642–650. 28) Shiina, I.; Suzuki, M.; Yokoyama, K. Tetrahedron Lett. 2004, 45, 965–967.
29) Shiina, I.; Sano, Y.; Nakata, K.; Suzuki, M.; Yokoyama, T.; Sasaki, A.; Orikasa, T.; Miyamoto, T.; Ikekita, M.; Nagahara, Y.; Hasome, Y. Bioorganic Med. Chem. 2007, 15, 7599–7617.
31) Takemoto, Y.; Yoshida, H.; Takaki, K. Chem. A Eur. J. 2012, 18, 14841–14844.
32) Zhou, Y.; You, W.; Smith, K. B.; Brown, M. K. Angew. Chem. Int. Ed. 2014, 53, 3475–3479. 33) Pichette Drapeau, M.; Fabre, I.; Grimaud, L.; Ciofini, I.; Ollevier, T.; Taillefer, M. Angew. Chem. Int. Ed. 2015, 54, 10587–10591.
34) Tollefson, E. J.; Hanna, L. E.; Jarvo, E. R. Acc. Chem. Res., 2015, 48 (8), pp 2344–2353. 35) Zhou, C.; Emrich, D. E.; Larock, R. C. Org. Lett. 2003, 5, 1579–1582.
36) Koyama, H.; Zhang, Z.; Ijuin, R.; Siqin; Son, J.; Hatta, Y.; Ohta, M.; Wakao, M.; Hosoya, T.; Doi, H.; Suzuki, M. RSC Adv. 2013, 3, 9391.
Acknowledgements
This work described in this chapter was carried out together with Milan van Zuylen and Filippo Tosi
8.7 Experimental section
All reactions were carried out under a nitrogen atmosphere using oven dried glassware and using standard Schlenk techniques unless noted otherwise. THF and toluene were dried using an SPS-system. White colored Pd(t-Bu3P)2, was purchased from Strem chemicals and stored under nitrogen
at -25 ºC. All alkyllithium reagents and aryl bromides were purchased from Aldrich or TCI and used without further purification, unless noted otherwise. Chromatography: Merck silica gel type 9385 230-400 mesh, TLC: Merck silica gel 60, 0.25 mm, or Grace-Reveleris purification system with Grace cartridges. Components were visualized by UV. Progress and conversion of the reaction were determined by GC-MS (GC, HP6890: MS HP5973) with an HP1 or HP5 column (Agilent Technologies, Palo Alto, CA). PREP-HPLC was perfomed on a Grace-reveleris PREP with a 5u Denali silica (15 cm, 10 mm id). 1H- and 13C-NMR were recorded on a Varian AMX400 (400 and 100.59 MHz, respectively) using CDCl3 as solvent, unless noted otherwise. Chemical shift values are reported in ppm with the solvent resonance as the internal standard (CHCl3: δ 7.26 for 1H, δ 77.0 for 13C) unless noted
otherwise. Data are reported as follows: chemical shifts, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constants (Hz), and integration. For quantitative analysis using 1H-NMR, 1,1,2,2-tetrachloroethane was used as an internal standard.
2-(4-Bromophenoxy)-N,N-dimethylethylamine (3)
To a dry Schlenk flask equipped with a stirring bar was added NaH (1.36 g (60%), 34 mmol) and washed twice with 5 mL of dry hexane, 5 mL of dry THF was added and the solution was cooled in an ice bath.
In a separate Schlenk flask 4-bromophenol (3.0 g, 17 mmol) was dissolved in 8 mL of dry THF. The resulting solution was added slowly to the flask containing the washed NaH as described above. After the addition was complete, the ice bath was removed, 2-chloro-N,N-dimethylethylamine hydrochloride (2.4 g, 17 mmol) was added in portions and the reaction mixture was heated to 40 °C. After 72 h the reaction mixture was allowed to cool to room temperature and the precipitate was filtered off. The filtrate was concentrated in vacuo and redissolved in 50 mL of ethyl acetate. The organic layer was extracted three times with 50 mL aq. 1M HCl and concentrated in vacuo. The aqueous layer was neutralized using aq. Na2CO3, and subsequently extracted three times with 100
mL EtOAc. The organic layer was then dried using Na2SO4 and concentrated in vacuo. Without further
purification a light brown liquid (4.2 g, 56%) was obtained. 1H-NMR (400 MHz, CDCl3) δ 7.36 (d, J = 8.9
Hz, 2H), 6.80 (d, J = 8.9 Hz, 2H), 4.03 (t, J = 5.7 Hz, 2H), 2.72 (t, J = 5.7 Hz, 2H), 2.33 (s, 6H). This spectrum is in accordance with literature.1
Tamoxifen ((Z)-1-(p-Dimethylaminoethoxyphenyl)-1,2-diphenyl-1-butene, trans-2-[4-(1,2-Diphenyl-1-butenyl)phenoxy]-N,N-dimethylethylamine) (4)
Preparation of lithio-stilbene: In a dry Schlenk flask (A) equipped with a stirring bar, 160 mg of diphenylacetylene (0.9 mmol) was dissolved in 1 mL of dry THF. The solution was cooled to 0 °C using an ice bath after which 1.85 mL of 0.5 M ethyllithium in
cyclohexane/benzene (0.93 mmol) was added dropwise to the solution. Upon addition, the solution turned orange. The solution was allowed to warm to room temperature and stirred for 3 h, during which it turned yellow, and finally, light green. To this solution was added 2 mL of dry toluene (Solution A)
To a dry Schlenk flask (B) equipped with a stirring bar was added Pd(t-Bu3P)2 (15.4 mg, 30 µmol, 5%)
and 2 mL of dry toluene. Using a syringe, 12 mL of dry oxygen was bubbled through the solution after which the solution was allowed to stir vigorously overnight, resulting in a deep red solution. A solution of compound 3 (146.4 mg, 0.6 mmol) in 1 mL of dry toluene was added to the flask. Solution A (freshly prepared) was added over the course of 20 min using a syringe pump. After the addition, the reaction mixture was quenched with 0.5 mL of MeOH, filtered over celite and concentrated in vacuo. The resulting liquid was dissolved in 20 mL of EtOAc and extracted four times with 30 mL of 1M aq. HCl. The aqueous layer was neutralized using Na2CO3 and subsequently extracted four times
with 50 mL of ethyl acetate. The organic layer was dried using Na2SO4 and concentrated in vacuo. The
crude yield was determined by 1H-NMR analysis, using 1,1,2,2-tetrachloroethane as an internal standard.
A fraction of the crude product was dissolved in a mixture of water/acetonitrile, and purified by RP (C18 Denali) Prep-HPLC chromatography (Water : Acetonitrile : TFA 50:49:1) 1H-NMR (400 MHz, CDCl3) δ 7.35 (d, J = 7.5 Hz, 2H), 7.25 (m, 2H), 6.76 (d, J = 8.8 Hz, 2H), 6.56 (d, J = 8.8 Hz, 1H), 3.92 (t, J
= 5.8 Hz, 2H), 2.64 (t, J = 5.8 Hz, 2H), 2.46 (q, J = 7.4 Hz, 2H), 2.28 (s, 6H), 0.92 (t, J = 7.4 Hz, 3H). This spectrum is in accordance with literature.2
(Z)-1-(1,2-diphenylhex-1-en-1-yl)naphthalene (8)
In a dry Schlenk flask (A) equipped with a stirring bar, diphenylacetylene (89 mg, 0.5 mmol) was dissolved in 1 mL of dry THF. The solution was cooled to 0 °C using an ice bath after which 0.37 mL of 1.5M n-butyllithium (0.55 mmol) was added dropwise to the solution. The solution was allowed to warm to room temperature and stirred for 2 h, resulting in a blue solution. To this solution was added 2 mL of dry toluene (Solution A).
To a dry Schlenk flask (B) equipped with a magnetic stirring bar and nitrogen line was added 11.9 mg of PEPPSI-IPent (15 µmol, 5%), 42 µL of 1-bromonaphthalene (62 mg, 0.3 mmol) and 3 mL of dry toluene. To this flask, solution A was added over the course of 20 min using a syringe pump. The resulting solution was quenched with a small amount of MeOH, filtered over celite and concentrated in vacuo. The conversion of the product was determined using GCMS (88%), Mass = 362.
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Sun, P. -P.; Cheng, Y. -C.; Chang, M. -Y. Synthesis 2017, 49 (11), pp. 2411-2422
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