Iterative Synthesis of Alkenes by Insertion of Lithiated Epoxides into

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Iterative Synthesis of Alkenes by Insertion of Lithiated Epoxides into Boronic Esters Kevin Bojaryn, Stefan Fritsch, and Christoph Hirschhäuser* Institut für Organische Chemie, Universität Duisburg-Essen, Universitätsstraße 7, 45141 Essen, Germany

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S Supporting Information *

ABSTRACT: The insertion of lithiated epoxides into boronic esters followed by thermal syn-elimination provides a stereospecific entry to alkenes. This process avoids transition metals and is amenable to iteration to provide higher substitution patterns.

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with a boronate and an electrophile in a stereospecific manner and form alkene 3 by anti-elimination. Aggarwal et al. recently expanded the scope of this chemistry by realizing a complementary syn-elimination strategy.5 Our initial attempts at preparing 1 involved synthons with reversed polarity compared to Pelter’s boron−Wittig reaction, i.e., a chiral carbanion and a boronate with an α-leaving group.6 By reacting a lithiated 2,4,6-triisopropylbenzoate with a racemic α-bromo boronate, a mixture of diastereomers of type 1 was generated. By first conducting the (faster) syn-elimination of the syn product followed by a TBAF induced anti elimation of the anti intermediate, the corresponding E-alkene was obtained (dr 4:1, see the Supporting Information). Blakemore et al. showed that by preparing the corresponding starting materials in an enantiomerically pure fashion, this approach allows for the stereospecific synthesis of trisubstituted olefins.7 However, none of these methods lends itself to iterative application. On the other hand, transition-metal-catalyzed cross couplings,8 in general, and Heck reactions, in particular,9 allow for direct functionalization of alkenes and can thus be applied in an iterative manner.10 However, cross-coupling methods suffer from problems due to competing β-hydride elimination when alkyl substrates are employed.9 This is not the case for our olefination protocol shown in Scheme 1B. Lithiation of epoxides like 4 and reaction with boronic esters provide intermediates of type 5,11 which then undergo thermal syn-elimination to alkenes 6. Since epoxides can be prepared in a stereospecific manner from alkenes by the Prilezhaev reaction,12 iterative application of this olefination is possible (e.g., 6 → 3). A likely mechanism for the epoxide olefination is shown in Scheme 2. Aggarwal et al. had described the transselective lithiation of epoxides of type 4 with LiTMP in the presence of pinacol boronic esters (2 equiv) in order to

any classical olefination reactions yield less than optimal results in terms of E/Z selectivity when higher substitution patterns are targeted.1 We are interested in the iterative and stereodefined synthesis of heteroatom-rich organoboron motifs of type 1.2 As these moieties can undergo stereospecific syn- or anti-elimination (1 → 3), we set out to develop an E/Z-selective olefination reaction that can be applied in an iterative manner. Previous approaches that involve preparation and elimination of precursors of type 1 are shown in Scheme 1A. The boron−Wittig reaction employs addition of α-lithiated boranes to aldehydes.3 Thus, the E/Z ratio of 3 is limited by the Felkin−Anh selectivity of this process. On the other hand, methods like the Zweifel olefination4 require the stereochemically defined preparation of appropriate vinylmetal precursors of type 2. These provide 1 Scheme 1. Transition-Metal-Free Olefinations Involving Boron

Received: February 8, 2019

© XXXX American Chemical Society

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DOI: 10.1021/acs.orglett.9b00517 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 3. Synthesis of Disubstituted Olefinsa

Scheme 2. Likely Mechanism for Epoxide Olefination

generate 1,2-diol derivatives.13 In this reaction, the resulting carbenoids14 of type 7 immediately form ate complexes (8), which undergo a stereospecific 1,2-metalate rearrangement. The resulting intermediates of type 5 are similar to Pelters3a aldol addition products of type 1 (Scheme 1A), but due to the excellent trans-selectivity, with which primary epoxides are lithiated, only one diastereomer is formed. In analogy to Pelters approach, we initially set out to intercept intermediates 5a (with R1 = R2 = Cy) with different acid chlorides in order to facilitate elimination,3 especially as a similar strategy using lithiated oxirane (R1 = H) had already been reported to yield a terminal alkene.13c For internal alkenes, however, our attempts led to unsatisfactory mixtures of 6a and its Z-congener. In one case, even a moderate selectivity for the Z-olefin was observed (see the Supporting Information). On the other hand, virtually complete trans-selectivity was achieved simply by heating. This is probably due to syn-elimination of either 5a itself or the ate complex 5b, which could be formed with excess boronate. In order to explore the substrate scope of the reaction, epoxides of type 4 and a variety of pinacol boronic esters (2 equiv)15 were reacted with LiTMP (2 equiv) in THF at 0 °C. The cooling bath was allowed to reach room temperature for 2 h or overnight before the temperature was raised to 60 °C for 2 h (Scheme 3).16 Monosubstituted epoxides with primary and secondary alkyl substituents react with primary or secondary alkyl pinacol boronic esters with yields between 55% and 68% (6a−c). The use of bulkier substituents led to diminished yields (6d,e). This probably reflects the steric hindrance of the tBu group, which could impair ate complex formation (7 → 8) or adoption of the ecliptic conformation necessary for synelimination of 5. On the other hand, phenyl pinacol boronic ester reacted even better under these conditions with various epoxides (6f−i). This is reasonably explained by swifter elimination to the conjugated alkene. The product obtained from reacting TBS-glycidyl ether with phenyl pinacol boronic ester (6i) was contaminated with an unidentified impurity. Furthermore, attempts to react this epoxide with cyclohexyl pinacol boronic ester failed completely (6j). TBS-glycidyl ether had been successfully inserted into alkyl boronic esters by Aggarwal et al.13a and after silylation and oxidation converted into a differentially protected diol. Thus, ate-complex formation and 1,2-rearrangement should occur under these conditions. However, after warming, the corresponding intermediate of type 5 Brook rearrangement could compete with the desired elimination.17,18 In comparison, the corresponding substrate in which the OTBS group was removed further from the epoxide underwent the olefination

a

No traces of the corresponding Z-diastereomers were observable by H NMR (pin = pinacol; LiTMP = lithium 2,2,6,6-tetramethylpiperidide; Cy = cyclohexyl; Oct = octyl). 1

reaction cleanly with both phenyl pinacol boronic ester and cyclohexyl pinacol boronic ester, in order to deliver 6k and 6l, respectively. The attempt to synthesize 6m from benzyloxymethyl pinacol boronic ester and cyclohexyloxirane also failed to produce the desired product and led to decomposition of the boronic ester. Because the boronic ester is present, when the base is added to the epoxide, competing lithiation of the CH-acidic boronate BnOCH2B(pin) is a likely explanation and serves to define the scope of this methodology.19 Again, a substrate with a more remote alkoxy group delivered the desired product (6n), although in comparatively low yield compared to the phenyl derivative 6f. All attempts to synthesize phthalimide derivatives of type 6o with a variety of boronic esters failed. Although the phthalimide moiety is compatible with amide bases,20 it can react as an electrophile and thus probably competes with the boronic ester as a scavenger for the lithiated epoxide. These results suggest that the reaction can proceed with a lot of substrates that do not have either (i) positions liable for competitive deprotonation or (ii) competing electrophilic positions. Thus, the substrate scope seems to be in line with the mechanism shown in Scheme 2. An attractive feature of this alkene synthesis is the facile preparation of the necessary epoxide reactants (4) from less substituted alkenes via Prilezhaev epoxidation.12 This also opens up the potential for iterative olefination reactions. As shown in Scheme 4, diastereoselective epoxidation of disubstituted alkenes to epoxides of type 9 was easily achieved in most cases.21 However, lithiation of disubstituted epoxides of type 9 opens up questions of regioselectivity. In the case of styrene derivatives like 9a, regioselective lithiation is easily achieved with sBuLi and TMEDA at −100 °C at the benzylic position, B

DOI: 10.1021/acs.orglett.9b00517 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 4. Synthesis of Trisubstituted Olefinsa

Scheme 5. Synthesis of Tetrasubstituted Olefinsa

a

(a) In these cases, the neopentyl boronic ester was used. (b) Isolated after 3 h (LiTMP = lithium 2,2,6,6-tetramethylpiperidide; Cy = cyclohexyl; PMP = p-methoxyphenyl, Oct = octyl).

and quenching with aromatic or aliphatic boronates delivers the corresponding trisubstituted alkenes in good yield and complete diastereoselectivity after heating to 38 °C overnight. We also briefly attempted to exploit the different steric demand of primary, secondary, and tertiary alkyl substituents in order to regioselectively direct lithiation. Therefore, epoxides 9c and 9d were prepared from 6c and 6d, respectively. Unfortunately, both compounds resisted lithiation at low temperatures and decomposed upon increasing temperature/reaction time, so that only traces of the resulting products 3f and 3g could be detected. For substrates with two identical substituents, the regioselectivity problem is avoided completely, as in the case of stilbene oxides of type 9b. The lithiated epoxide intermediate formed from transstilbene oxide (9b-trans) and nBuLi in THF at −60 °C22 was converted into the corresponding E-alkenes 3c-E and 3d-E after addition of primary or secondary alkyl boronates and heating to 60 °C for 2 h. In analogy, cis-stilbene oxide (9b-cis) was converted into Z-alkenes 3c-Z and 3d-Z. This is in agreement with the mechanism suggested in Scheme 2, in which both the 1,2-migration and the syn-elimination are stereospecific steps. Olefins 3c-E and 3d-E were isolated only in moderate yield, and the samples were contaminated with traces of the undesired diastereomer (de = 95% and de = 94%, respectively). However, the olefins derived from cis-stilbene oxide (3c-Z and 3d-Z) were produced in excellent yield and without any formation of the corresponding E-isomers detectable by 1H NMR (de > 95%). The difference in yield could reflect the more facile lithiation of cis-stilbene oxide as well as a less hindered attack of the boronate electrophile. In addition, the oxirane of trans-stilbene oxide can facilitate directed ortho metalation.22 Scheme 5 comprises attempts to apply this method to tetrasubstituted alkenes. Therefore, olefins of type 3-Z and 3-E were both converted into the corresponding epoxides 10-cis and 10-trans, respectively. While sterically accessible epoxides of type 10-cis could be lithiated

a

All products that could be obtained had a de > 95%. (a) Yield obtained by NMR using an internal standard. (b) Although 1H NMR suggested that only one diastereomer was formed, the absolute stereochemistry of 14 remains uncertain, as the material decomposed in CDCl3 before complete characterization was achieved. (c) Lithiation was attempted at −98 °C (Cy = cyclohexyl; PMP = pmethoxyphenyl, Oct = octyl).

and converted into the tetrasubstituted olefins 11b−g (Scheme 5A), epoxides of type 10-trans resisted lithiation (Scheme 5B). No conversion of epoxides of type 10-trans was observed upon addition of alkyllithium bases under a variety of conditions (see the Supporting Information). The use of Schlosser’s base, however, converted the epoxide 10a-trans (R3 = Cy) cleanly into ketone 13. Thus, the (more ionic) potassium intermediate 12 apparently underwent intramolecular decomposition before intermolecular reaction with a boronic ester could occur.23 Formation of an enolate intermediate was confirmed by TMSCl quench. However, the TMS ether 14 was quite unstable, and decomposition in CDCl3 to ketone 13 occurred before complete characterization was achieved. Finally, we applied the olefination method to the synthesis of E-tamoxifen (Scheme 5C). Starting from cis-stilbene oxide 9b-cis the trisubstituted epoxide 10c-cis was prepared by direct alkylation of the lithiated epoxide. This direct approach saves a step in comparison to an olefination epoxidation sequence (9 → 3 → 10) like the one employed for the cyclohexyl or butyl congeners 10a-cis and 10b-cis. However, it should be mentioned that this requires a good electrophile like ethyl iodide. Direct alkylation of lithiated stilbene oxide was described to occur after deprotonation with nBuLi and reaction with ethyl iodide.22 In our hands, however, this led C

DOI: 10.1021/acs.orglett.9b00517 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Notes

to a mixture of ethylated and butylated products. This was probably due to an iodolithium exchange (Bu-Li + Et-I → Bu-I + Et-Li) with unreacted butyllithium. This was avoided by using sBuLi, so that 10c-cis was obtained with 94% yield and, judging by 1H NMR, complete diastereomeric purity. After a brief optimization, lithiation and olefination to the tetrasubstituted olefins 11e and 11f were achieved in 41% and 87% yield, respectively. The anisole derivative 11f can be converted into E-tamoxifen 11g.24 However, E-tamoxifen 11g can also be prepared directly by reaction of lithiated 10c-cis with the appropriate boronic ester, which contains an ether and a tertiary amine functionality. That way, E-tamoxifen 11g can be prepared in only two steps from cis-stilbene oxide 9b-cis in 59% overall yield. In conclusion, lithiated epoxides insert readily into boronic esters, which can be exploited for the stereoselective synthesis of olefins. The high degree of diastereoselectivity, which can be achieved in epoxide lithiation, translates into excellent diastereomeric excesses in the formation of di-, tri-, and even tetrasubstituted alkenes. In fact, only in two cases (3c-E and 3d-E) were small amounts of the undesired alkene detected. In both of these cases, neither contamination of the starting epoxide nor subsequent E/Z-isomerization of the alkene can be excluded. As one would expect, reaction conditions do not allow for the availability of protons of comparable acidity (6m) or electrophilic positions (6o) in the reaction mixture. Iterative application can be achieved after Prilezhaev epoxidation and renewed lithiation. The lithiation of di- and trisubstituted epoxides was only achieved effectively in benzylic positions, so that disubstituted styrene (3a−d) and stilbene derivatives (11b−g) could be synthesized. Reactions with unsubstituted trans-stilbene oxide (9b-trans) delivered lower yields than with cis-stilbene oxide (9b-cis), and substituted trans-stibene oxide derivatives (10-trans) were resistant toward lithiation and underwent decomposition upon deprotonation with Schlosser’s base. It is likely that this limitation is mainly due to the reluctance of these substrates toward lithiation, as comparable epoxides lithiated by other means could be inserted successfully into boronic esters.25 Future studies will attempt to exploit this difference in reactivity in order to increase the scope of this reaction for the synthesis of higher substitution patterns. The iterative applicability of this chemistry makes it potentially useful for the synthesis of compound libraries of pharmaceutically interesting olefins as showcased by the synthesis of E-tamoxifen.

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The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank Prof. Dr. Carsten Schmuck from the University of Duisburg and Essen for his kind support, Prof. Dr. Tim Gallagher from the University of Bristol for constructive discussions, and the Deutsche Forschungsgemeinschaft (DFG) for funding.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b00517.

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REFERENCES

(1) (a) Blakemore, P. R. In Comprehensive Organic Synthesis II; 2nd ed.; Knochel, P., Ed.; Elsevier: Amsterdam, 2014; pp 516−608. (b) Wang, J. In Topics in Current Chemistry; Springer: Heidelberg, 2012. (c) Williams, J. M. J. Preparation of Alkenes: A Practical Approach; Oxford University Press: Oxford, 1996. (d) Flynn, A. B.; Ogilvie, W. W. Chem. Rev. 2007, 107, 4698−4745. (2) (a) Kirupakaran, S.; Korth, H.-G.; Hirschhäuser, C. Synthesis 2018, 50, 2307−2322. (b) Struth, F. R.; Hirschhäuser, C. Eur. J. Org. Chem. 2016, 2016, 958−964. (3) (a) Pelter, A.; Smith, K.; Elgendy, S.; Rowlands, M. Tetrahedron Lett. 1989, 30, 5647−5650. (b) Pelter, A.; Buss, E.; Colclough, E. J. Chem. Soc., Chem. Commun. 1987, 0, 297−299. (c) Matteson, D. S.; Moody, R. J.; Jesthi, P. K. J. Am. Chem. Soc. 1975, 97, 5608−5609. (d) Coombs, J. R.; Zhang, L.; Morken, J. P. Org. Lett. 2015, 17, 1708−1711. (4) (a) Zweifel, G.; Arzoumanian, H.; Whitney, C. C. J. Am. Chem. Soc. 1967, 89, 3652−3653. (b) Recent review: Armstrong, R. J.; Aggarwal, V. K. Synthesis 2017, 49, 3323−3336. (5) (a) Armstrong, R. J.; García-Ruiz, W.; Myers, E. L.; Aggarwal, V. K. Angew. Chem., Int. Ed. 2017, 56, 786−790. Also see: (b) Armstrong, R. J.; Niwetmarin, W.; Aggarwal, V. K. Org. Lett. 2017, 19, 2762−2765. (6) Matteson, D. S.; Tripathy, P. B.; Sarkar, A.; Sadhu, K. M. J. Am. Chem. Soc. 1989, 111, 4399−4402. (7) Wu, Z.; Sun, X.; Potter, K.; Cao, Y.; Zakharov, L. N.; Blakemore, P. R. Angew. Chem., Int. Ed. 2016, 55, 12285−12289. (8) Negishi, E.; Huang, Z.; Wang, G.; Mohan, S.; Wang, C.; Hattori, H. Acc. Chem. Res. 2008, 41, 1474−1485. (9) (a) Heck, R. F. Org. React. 1982, 27, 345. (b) Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009. (c) Coeffard, V.; Guiry, P. J. Curr. Org. Chem. 2010, 14, 212. (d) Ruan, J.; Xiao, J. Acc. Chem. Res. 2011, 44, 614. (e) Mc Cartney, D.; Guiry, P. J. Chem. Soc. Rev. 2011, 40, 5122. (10) (a) He, Z.; Kirchberg, S.; Fröhlich, R.; Studer, A. Angew. Chem., Int. Ed. 2012, 51, 3699−3702. (b) Li, J.; Ballmer, S. G.; Gillis, E. P.; Fujii, S.; Schmidt, M. J.; Palazzolo, A. M. E.; Lehmann, J. W.; Morehouse, G. F.; Burke, M. D. Science 2015, 347, 1221−1226. (11) All chiral compounds were prepared racemic. However, in Schemes 1−5, only one enantiomer of such compounds is shown. (12) Prileschajew, N. Ber. Dtsch. Chem. Ges. 1909, 42, 4811−4815. (13) (a) Vedrenne, E.; Wallner, O. A.; Vitale, M.; Schmidt, F.; Aggarwal, V. K. Org. Lett. 2009, 11, 165−168. (b) Armstrong, R. J.; Aggarwal, V. K. Org. Synth. 2017, 94, 234−251. (c) Pulis, A. P.; Aggarwal, V. K. J. Am. Chem. Soc. 2012, 134, 7570−757. (14) Review on alkene syntheses with carbenoids: (a) Blakemore, P. R.; Hoffmann, R. W. Angew. Chem., Int. Ed. 2018, 57, 390−407. Review on lithiated epoxides: (b) Hodgson, D. M.; Gras, E. Synthesis 2002, 2002, 1625−1642. (c) Capriati, V.; Florio, S.; Luisi, R. Chem. Rev. 2008, 108, 1918−1942. (15) The need for 2 equiv for the rearrangement to occur under these conditions was recognized in ref 13a and is discussed here: Bojaryn, K.; Hoffmann, C.; Struth, F. R.; Hirschhäuser, C. Synlett 2018, 29, 1092−1094. (16) The use of temperature regime A or B is a matter of convenience, as shown for 6a. Lithiation can also be performed at −30 °C (C) as shown for 6g. This can be useful when competing side

Preceding experiments, detailed experimental procedures, characterization data and copies of NMR spectra for all products (PDF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Christoph Hirschhäuser: 0000-0002-9409-1550 D

DOI: 10.1021/acs.orglett.9b00517 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters reactions are an issue (6i). Prolonged heating at 60 °C led to diminished yields of 6f. (17) A competing Brook rearrangement18 would be consistent with the observation that the conjugated alkene 6i formed, while the isolated alkene in 6j did not. One would expect elimination to a conjugated olefin to be much faster. Thus, in the conjugated case, olefin formation might compete with a Brook rearrangement (followed by decomposition), while the latter process is faster in the case of R2Cy.

(18) Brook, A. G. Acc. Chem. Res. 1974, 7, 77−84. (19) As shown by Hodgson19a and Aggarwal13 LiTMP is a sterically demanding base, which can be used to deprotonate epoxides in the presence of electrophiles. That way, in situ trapping prevents decomposition of carbenoid 7. Lithiation and quench can be performed in a consecutive manner but requires additional stabilization of the carbenoid, e.g., by a chiral diamine.19b (a) Hodgson, D. M.; Reynolds, N. J.; Coote, S. J. Tetrahedron Lett. 2002, 43, 7895−7897. (b) Hodgson, D. M.; Kirton, E. H. M.; Miles, S. M.; Norsikian, S. L. M.; Reynolds, N. J.; Coote, S. J. Org. Biomol. Chem. 2005, 3, 1893−1904. (20) Green, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis; Wiley-Interscience: New York, 1999; pp 564−566, 740− 743. (21) Electron rich olefins like the PMP derivative 6n underwent epimerization. See the Supporting Information. (22) Florio, S.; Aggarwal, V.; Salomone, A. Org. Lett. 2004, 6, 4191− 4194. (23) Ketone formation can be rationalized in two ways: either as the product of an E1cb elimination of 12 or through carbene formation followed by a 1,2-migration of the cyclohexyl sustituent. (24) Al-Hassan, M. I. Synth. Commun. 1987, 17, 1247−1251. (25) (a) Shimizu, M.; Fujimoto, T.; Minezaki, H.; Hata, T.; Hiyama, T. J. Am. Chem. Soc. 2001, 123, 6947−6948. (b) Alwedi, E.; Zakharov, L. N.; Blakemore, P. R. Eur. J. Org. Chem. 2014, 2014, 6643−6648.

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DOI: 10.1021/acs.orglett.9b00517 Org. Lett. XXXX, XXX, XXX−XXX