Regio- and Stereoselective Alkenylation of Allenoates with gem

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

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Regio- and Stereoselective Alkenylation of Allenoates with gemDifluoroalkenes: Facile Access to Fluorinated 1,4-Enynes Bearing an All-Carbon Quaternary Center Qi-Qi Zhang,† Shi-Yong Chen,† E Lin,† Honggen Wang,† and Qingjiang Li*,†,‡ †

School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China

‡

Org. Lett. Downloaded from pubs.acs.org by IDAHO STATE UNIV on 04/12/19. For personal use only.

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ABSTRACT: A regio- and stereoselective synthesis of fluorinated 1,4-enynes bearing an all-carbon quaternary center at the propargylic position is developed. The synthesis starts from readily available allenoates and gem-difluoroalkenes and proceeds via a key alkynylenolate intermediate following a nucleophilic addition/β-F elimination. This reaction occurs under mild reaction conditions with good tolerance to a variety of functional groups. Synthetic utility is demonstrated by further transformations of the products. Furthermore, the reaction can also be applied for the synthesis of α-alkenyl allenoates by using 3,3-disubstituted allenoates. Scheme 1. α-Selective Functionalization of Allenoates

A

lkenes and alkynes are of pivotal importance in organic chemistry due to their versatility as synthons in synthetic transformations.1 1,n-Enynes, with an alkenyl moiety attached to an alkyne, show unique reactivities as examplied by their involvement in intriguing cyclization reaction by metalcatalyzed cyclization (or cycloisomerization) processes2 and radical cascade transformations.3 In this regard, 1,4-enynes are of particular value in organic synthesis and therefore gain much endeavor toward their construction.4 Nevertheless, the 1,4enynes deconjugated by an all-carbon quaternary center5 represent a type of challenging target, and only a handful of methods exist for their preparation. Allenoates are readily available6 and have been widely explored as intriguing synthons in organic transformations. Specifically, upon base-promoted allenylic deprotonation, the 3-monosubstituted allenoates can be converted to the alkynylenolate intermediates (Scheme 1), which can react with diverse electrophiles to provide the α-functionalized products bearing an all-carbon quaternary center under kinetic control. Examples such as SN2-type alkylation,7 Michael addition,8 SNAr arylation,9 and aldol condensation,10 among others,11 were known (Scheme 1a−d). On the one hand, by proper choosing of coupling partners, the thermodynamically favored γ-functionalization of 3-monosubstituted allenoates is also feasible.12 On the other hand, gem-difluoroalkenes13 are electron-deficient fluorinated unsaturated system, which have been employed in diverse organofluorine syntheses. The © XXXX American Chemical Society

notable inductive effect of the fluorine atoms along with the electron repulsion between the double bond and the fluorine atoms render the α carbon in gem-difluoroalkenes highly electrophilic and susceptible for nucleophilic attack.14 Thus, a Received: March 1, 2019

A

DOI: 10.1021/acs.orglett.9b00775 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters number of oxygen, nitrogen, sulfur, or even carbon-centered nucleophiles were known to undergo addition−elimination reactions to provide diversely substituted monofluoroalkenes with or without a stereoselective manner.15 Alternatively, instead of β-F elimination, a nucleophilic hydrofunctionalization reaction of difluoroalkene would possibly deliver a gemdifluorinated product.16 In continuation with our interest in gem-difluoroalkene chemistry,17 we envisioned this electrophilic species might serve as an intriguing coupling partner when reacting with allenoates to deliver fluorinated 1,4-enynes. Interestingly, the α-alkenylation of 3-monosubstituted allenoates has not been reported thus far. Herein, we disclose our realization of a base-promoted regio- and stereoselective alkenylation of allenoates with gem-difluoroalkenes via a nucleophilic addition/β-F elimination mechanism. The reaction leads to the mild and facile synthesis of fluorinated 1,4enynes bearing an all-carbon quaternary center at the propargylic position in good efficiency (Scheme 1e). We initiated our studies by examining the influence of different bases and solvents in the reaction of α-methyl-γphenyl-allenoate 1a with gem-difluoroalkene 2a at room temperature (rt). The representative results are summarized in Table 1. When tetra-n-butylammonium fluoride (TBAF), a

undec-7-ene (DBU), lithium diisopropylamide (LDA), or lithium bis(trimethylsilyl)amide (LHMDS) did not promote the desired alkenylation either (entries 2−4). To our delight, tert-butanolate or trimethylsilanolate as base in acetonitrile successfully delivered the desired product (entries 5−7), with lithium tert-butanolate being the best (75%, entry 6). The Z geometry of the introduced double bond was determined by its 3 JH−F coupling constant in the 1H NMR spectrum (ca. 37.0 Hz for the Z isomer). Of note, only a trace amount of other undefined isomers were detected by gas chromatography− mass spectrometry (GC-MS). The use of inorganic bases such as K2CO3 or NaOH was proven to be unsuccessful (entries 8 and 9). The solvent effect was also examined. While dimethyl sulfoxide (DMSO) and dimethylformamide (DMF) (polar aprotic solvent) exhibited comparable efficiency (entries 10 and 11), other solvents, such as dichloromethane (DCM), Et2O, and 1,4-dioxane gave trace or no desired product (entries 12−14). Inferior results were obtained when increasing the reaction temperature to 50 °C (entry 15). With the optimized conditions in hand (Table 1, entry 6), the scope of the regio- and stereoselective alkenylation reaction with respect to allenoates was then investigated, and the results were summarized in Scheme 2. The effect of the R1 group at γ

Table 1. Optimization of the Reaction Conditionsa

Scheme 2. Substrate Scope of Allenoates 1a

entry

base

solvent

yieldb (%)

c

TBAF DBU LDA Li[N(TMS)2] t-BuOK t-BuOLi Me3SiOK K2CO3 NaOH t-BuOLi t-BuOLi t-BuOLi t-BuOLi t-BuOLi t-BuOLi

MeCN MeCN THF THF MeCN MeCN MeCN MeCN MeCN DMSO DMF DCM Et2O 1,4-dioxane MeCN

trace 0 0 0 63 75 60 trace trace 70 72 trace 0 0 48

1 2 3d 4d 5 6 7 8 9 10 11 12 13 14 15e a

General reaction conditions: 1a (0.2 mmol, 1.0 equiv), 2a (0.3 mmol, 1.5 equiv), base (2.0 equiv), solvent (2.0 mL), rt, 1 h. bIsolated yield. c1.0 M solution in tetrahydrofuran (THF). dConducted at −45 °C to rt. eConducted at 50 °C.

frequently used organic base in alkynylenolate chemistry,7c,8b,9,12b was employed, only trace amount of desired alkenylation product was detected (entry 1). Instead, a nucleophilic addition reaction of F− to gem-difluoroalkene 2a occurred, predominantly giving a hydrofluorination product 4 (eq 1).16b Other organic bases such as 1,8-diazabicyclo[5.4.0]-

a

General reaction conditions: 1 (0.2 mmol, 1.0 equiv), 2a (0.3 mmol, 1.5 equiv), t-BuOLi (2.0 equiv), CH3CN (2.0 mL), rt, 1 h under N2, isolated yield. bYield in parentheses based on the recovered starting material. cThe ratio to other isomers was determined by 19F NMR.

position was first examined. The reaction proceeded smoothly for both aromatic (3aa, 3ba) and aliphatic (3ca-3ha) substrates, furnishing the corresponding 1,4-enyne products in generally moderate to good yields. A lower yield of 38% was observed when t-butyl-substituted allenoate (3fa) was employed, probably for steric reasons. The synthesis of terminal alkynes is an important but challenging topic in B

DOI: 10.1021/acs.orglett.9b00775 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters organic chemistry. To our great surprise, by reacting 1,1disubstituted allenoate 1i with 2a, the desired terminal alkyne 3ia was obtained in good yield (68%). Next, the scope on R2 and the ester group were also explored. Valuable functional groups such as benzyl (3ka), allyl (3la, 3ma), and propargyl (3na, 3pa) were well-tolerated, and the corresponding highly unsaturated products were obtained in moderate yields. The use of methyl ester did not affect the reactivity (3pa), whereas the sterically demanding t-butyl ester gave a relatively lower yield (3qa). It was noted that the ratio of the desired Z-1,4enyne product to other isomers was more than 20:1 in most cases. The scope of the reaction with respect to aryl gemdifluoroalkenes 2 was also explored by changing the solvent to DMSO (Scheme 3). Not unexpectedly, the reaction is quite

difluoroalkene 2a under the standard reaction conditions with slightly higher yield (50%, Scheme 4a). In addition, Scheme 4. Gram-Scale Synthesis and Synthetic Transformations of the Products

Scheme 3. Substrate Scope of Aryl gem-Difluoroalkenes 2a

a

General reaction conditions: 1k (0.2 mmol, 1.0 equiv), 2 (0.3 mmol, 1.5 equiv), t-BuOLi (2.0 equiv), DMSO (2.0 mL), rt, 1 h under N2, isolated yield. bYield in parentheses based on the recovered starting material. cThe ratio to other isomers was determined by 1H NMR. d The ratio to other isomers was determined by 19F NMR.

synthetic decoration of the formed products led to a series of complex monofluoroalkenylated structures. For instance, upon treatment with Pd/H2, the stereoselective hydrogenation of C−C triple bond of 3ja gave 1,4-diene 7 in 50% yield (Scheme 4b, right). Starting from the same substrate, the functionalized γ-lactone 8 was obtained in 65% yield via a mild and efficient I2-mediated electrophilic cyclization reaction (Scheme 4b, left). 1,3-Cyclohexadiene 9 could be readily obtained directly from 1,5-enyne 3la by the use of a catalytic amount of a gold complex activated by silver hexafluoroantimonate (Scheme 4c).19 Finally, the Cu-catalyzed [3 + 2] cycloaddition of terminal alkyne 3ia with BnN3 10 gave the corresponding triazole 11 (Scheme 4d, not optimized yield).20 In summary, we have developed a simple and efficient method for the construction of 1,4-enynes bearing an allcarbon quaternary center. The appended acetylene, monofluoroalkene, and ester groups are useful functionalities for further transformations. The approach, starting from readily available allenoates and gem-difluoroalkenes, proceeds in a regio- and stereoselective manner under mild reaction conditions, with good tolerance to a variety of functional groups and moderate to good yields being observed. The synthetic utility of the reaction was demonstrated by a practical gram-scale synthesis and further transformations of the products to attractive structural motifs such as 1,4-diene, γlactone, 1,3-cyclohexadiene, and triazole. In addition, the reaction can also be applied for the synthesis of α-alkenyl allenoates by using 3,3-disubstituted allenoates. In consideration of the ready availability of the starting materials and the importance of the 1,4-enynes and fluorine atom, we anticipate this method will find applications in organic synthesis.

sensitive to the electronic properties of the substituents on the benzene ring. While the use of electron-donating substituents led to low yields, electron-withdrawing substituents were generally tolerated in the reaction. Thus, irrespective of the substituted position, substituents such as ester (3kb), trifluoromethyl (3kc), bromo (3kd, 3kg, 3kj), chloro (3kf, 3kh, 3ki), and fluoro (3kk) yielded the corresponding products with good efficiency. The reaction of nitrosubstituted gem-difluoroalkene (3ke) gave a lower yield. Of note, steric hindrance at the 2-position of benzene ring was also tolerated well (3ke-3kj). Since the α-proton of 3,3-disubstituted allenoates could also be easily removed by a base, this sequentially prompted us to explore the reactivity of 3,3-disubstituted allenoates with gemdifluoroalkenes. As expected, the method can also be applied for the synthesis of α-alkenyl allenoates18 by using 3,3disubstituted allenoates as substrates. Thus, γ-phenyl-γ-methyl or γ-phenyl-γ-ethyl allenoates 5 successfully underwent an αselective alkenylation reaction under our standard conditions to deliver the corresponding α-monofluoroalkenyl allenoates 6, albeit lower yields were observed at present (eq 2). The low yields rose from the large amounts of unreacted starting materials. A gram-scale synthesis was performed to demonstrate the practicality of this reaction. Thus, 1.02 g of 1,4-enyne 3la was obtained via the alkenylation of allenoate 1l with gemC

DOI: 10.1021/acs.orglett.9b00775 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

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(8) (a) Martzel, T.; Lohier, J.-F.; Gaumont, A.-C.; Brière, J.-F.; Perrio, S. Adv. Synth. Catal. 2017, 359, 96. (b) Liu, L.-P.; Xu, B.; Hammond, G. B. Org. Lett. 2008, 10, 3887. (9) Jana, S.; Roy, A.; Lepore, S. D. Chem. Commun. 2017, 53, 5125. (10) Bang, J.; Oh, C.; Lee, E.; Jeong, H.; Lee, J.; Ryu, J. Y.; Kim, J.; Yu, C.-M. Org. Lett. 2018, 20, 1521. (11) Yang, H.; Xu, B.; Hammond, G. B. Org. Lett. 2008, 10, 5589. (12) Selected examples for theγ-functionalization of 3-monosubstituted allenoates, see: (a) Hashimoto, T.; Sakata, K.; Tamakuni, F.; Dutton, M. J.; Maruoka, K. Nat. Chem. 2013, 5, 240. (b) Xu, B.; Hammond, G. B. Angew. Chem., Int. Ed. 2008, 47, 689. (c) Tap, A.; Blond, A.; Wakchaure, V. N.; List, B. Angew. Chem., Int. Ed. 2016, 55, 8962. (d) Mbofana, C. T.; Miller, S. J. J. Am. Chem. Soc. 2014, 136, 3285. (e) Wang, M.; Fang, Z.; Fu, C.; Ma, S. Angew. Chem., Int. Ed. 2014, 53, 3214. (f) Wang, G.; Liu, X.; Chen, Y.; Yang, J.; Li, J.; Lin, L.; Feng, X. ACS Catal. 2016, 6, 2482. (g) Selig, P.; Turočkin, A.; Raven, W. Synlett 2013, 24, 2535. (13) Zhang, X.; Cao, S. Tetrahedron Lett. 2017, 58, 375. (14) O’Hagan, D. Chem. Soc. Rev. 2008, 37, 308. (15) For selected recent articles, see: (a) Xiong, Y.; Zhang, X.; Huang, T.; Cao, S. J. Org. Chem. 2014, 79, 6395. (b) Dai, W.; Shi, H.; Zhao, X.; Cao, S. Org. Lett. 2016, 18, 4284. (c) Zhang, J.; Xu, C.; Wu, W.; Cao, S. Chem. - Eur. J. 2016, 22, 9902. (d) Landelle, G.; Champagne, P. A.; Barbeau, X.; Paquin, J.-F. Org. Lett. 2009, 11, 681. (e) Thornbury, R. T.; Toste, F. D. Angew. Chem., Int. Ed. 2016, 55, 11629. (f) Zhang, J.; Dai, W.; Liu, Q.; Cao, S. Org. Lett. 2017, 19, 3283. (g) Yu, L.; Tang, M.-L.; Si, C.-M.; Meng, Z.; Liang, Y.; Han, J.; Sun, X. Org. Lett. 2018, 20, 4579. (h) Lu, X.; Wang, Y.; Zhang, B.; Pi, J.-J.; Wang, X.-X.; Gong, T.-J.; Xiao, B.; Fu, Y. J. Am. Chem. Soc. 2017, 139, 12632. (i) Sakaguchi, H.; Uetake, Y.; Ohashi, M.; Niwa, T.; Ogoshi, S.; Hosoya, T. J. Am. Chem. Soc. 2017, 139, 12855. (j) Kong, L.; Zhou, X.; Li, X. Org. Lett. 2016, 18, 6320. (k) Xie, J.; Yu, J.; Rudolph, M.; Rominger, F.; Hashmi, A. S. K. Angew. Chem., Int. Ed. 2016, 55, 9416. (l) Zell, D.; Dhawa, U.; Muller, V.; Bursch, M.; Grimme, S.; Ackermann, L. ACS Catal. 2017, 7, 4209. (m) Tian, P.; Feng, C.; Loh, T.-P. Nat. Commun. 2015, 6, 7472. (o) Wang, M.; Liang, F.; Xiong, Y.; Cao, S. RSC Adv. 2015, 5, 11996. (p) Cong, Z.S.; Li, Y.-G.; Chen, L.; Xing, F.; Du, G.-F.; Gu, C.-Z.; He, L. Org. Biomol. Chem. 2017, 15, 3863. For a review, see: (q) Landelle, G.; Bergeron, M.; Turcotte-Savard, M.-O.; et al. Chem. Soc. Rev. 2011, 40, 2867. (16) (a) Orsi, D. L.; Easley, B. J.; Lick, A. M.; Altman, R. A. Org. Lett. 2017, 19, 1570. (b) Qiao, Y.; Si, T.; Yang, M.-H.; Altman, R. A. J. Org. Chem. 2014, 79, 7122. (17) (a) Wu, J.-Q.; Zhang, S.-S.; Gao, H.; Qi, Z.; Zhou, C.-J.; Ji, W.W.; Liu, Y.; Chen, Y.; Li, Q.; Li, X.; Wang, H. J. Am. Chem. Soc. 2017, 139, 3537. (b) Ji, W.-W.; Lin, E.; Li, Q.; Wang, H. Chem. Commun. 2017, 53, 5665. (c) Yang, L.; Ji, W.-W.; Lin, E.; Li, J.-L.; Fan, W.-X.; Li, Q.; Wang, H. Org. Lett. 2018, 20, 1924. (d) Tan, D.-H.; Lin, E.; Ji, W.-W.; Zeng, Y.-F.; Fan, W.-X.; Li, Q.; Gao, H.; Wang, H. Adv. Synth. Catal. 2018, 360, 1032. (e) Yang, L.; Fan, W.-X.; Lin, E.; Tan, D.-H.; Li, Q.; Wang, H. Chem. Commun. 2018, 54, 5907. (18) There is only one example reported for the synthesis of αalkenylallenoate currently: Kimura, T.; Kobayashi, G.; Ishigaki, M.; Inumaru, M.; Sakurada, J.; Satoh, T. Synthesis 2012, 44, 3623. (19) Gorin, D. J.; Dubé, P.; Toste, F. D. J. Am. Chem. Soc. 2006, 128, 14480. (20) Sharpless, W. D.; Wu, P.; Hansen, T. V.; Lindberg, J. G. J. Chem. Educ. 2005, 82, 1833.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b00775.

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Detailed experimental procedures, characterization of all reported compounds, and 1H, 13C, and 19F NMR spectra (PDF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] ORCID

Shi-Yong Chen: 0000-0003-1824-5404 Honggen Wang: 0000-0002-9648-6759 Qingjiang Li: 0000-0001-5535-6993 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful for the support of this work by the National Natural Science Foundation of China (21502242 and 81402794) and the State Key Laboratory of Natural and Biomimetic Drugs (K20150215).

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REFERENCES

(1) For selected reviews and books, see: (a) Remy, R.; Bochet, C. G. Chem. Rev. 2016, 116, 9816. (b) McDonald, R. I.; Liu, G.; Stahl, S. S. Chem. Rev. 2011, 111, 2981. (c) Willis, M. C. Chem. Rev. 2010, 110, 725. (d) Diederich, F.; Stang, P. J.; Tykwinski, R. R. Acetylene Chemistry; Wiley-VCH: New York, 2005. (e) Tiwari, V. K.; Mishra, B. B.; Mishra, K. B.; Mishra, N.; Singh, A. S.; Chen, X. Chem. Rev. 2016, 116, 3086. (2) (a) Michelet, V.; Toullec, P. Y.; Genêt, J.-P. Angew. Chem., Int. Ed. 2008, 47, 4268. (b) Jiménez-Núñez, E.; Echavarren, A. M. Chem. Rev. 2008, 108, 3326. (c) Villar, H.; Frings, M.; Bolm, C. Chem. Soc. Rev. 2007, 36, 55. (d) Zhang, L.; Sun, J.; Kozmin, S. A. Adv. Synth. Catal. 2006, 348, 2271. (e) Diver, S. T.; Giessert, A. J. Chem. Rev. 2004, 104, 1317. (3) A very recent review, see: Xuan, J.; Studer, A. Chem. Soc. Rev. 2017, 46, 4329. (4) A review about the application of 1,4-enynesin rhodiumcatalyzed [5 + 2] cycloadditions, see: Schienebeck, C. M.; Li, X.; Shu, X.-Z.; Tang, W. Pure Appl. Chem. 2014, 86, 409. (5) Scattered examples for the synthesis of α-alkenyl-α-alkynyl esters, see: (a) Hashimoto, T.; Sakata, K.; Maruoka, K. Adv. Synth. Catal. 2010, 352, 1653. (b) Liu, Y.; Yu, Q.; Ma, S. Eur. J. Org. Chem. 2013, 2013, 3033. (c) Dabrowski, J. A.; Gao, F.; Hoveyda, A. H. J. Am. Chem. Soc. 2011, 133, 4778. (d) Hata, S.; Koyama, H.; Shimizu, M. J. Org. Chem. 2011, 76, 9670. (e) Yao, Y.; Li, J.-L.; Zhou, Q.-Q.; Dong, L.; Chen, Y.-C. Chem. - Eur. J. 2013, 19, 9447. (f) Hatano, M.; Yamashita, K.; Mizuno, M.; Ito, O.; Ishihara, K. Angew. Chem., Int. Ed. 2015, 54, 2707. (g) Lee, J.-H.; Park, J.-S.; Cho, C.-Y. Org. Lett. 2002, 4, 1171. (6) Krause, N.; Hashmi, A. S. Modern Allene Chemistry; Wiley-VCH: Weinheim, Germany, 2004. (7) (a) Tokuda, M.; Nishio, O. J. Org. Chem. 1985, 50, 1592. (b) Hashimoto, T.; Sakata, K.; Maruoka, K. Angew. Chem., Int. Ed. 2009, 48, 5014. (c) Kitagaki, S.; Teramoto, S.; Mukai, C. Org. Lett. 2007, 9, 2549. (d) Wang, W.; Xu, B.; Hammond, G. B. Org. Lett. 2008, 10, 3713. (e) Nanayakkara, P.; Alper, H. J. Org. Chem. 2004, 69, 4686. D

DOI: 10.1021/acs.orglett.9b00775 Org. Lett. XXXX, XXX, XXX−XXX