Letter pubs.acs.org/OrgLett
Regio- and Stereoselective Anti-Carbozincation of Alkynyl Ethers Using ZnBr2 toward (Z)-β-Zincated Enol Ether Synthesis Yoshihiro Nishimoto,*,† Kyoungmin Kang,‡ and Makoto Yasuda*,‡ †
Frontier Research Base for Global Young Researchers, Center for Open Innovation Research and Education (COiRE), Graduate School of Engineering, and ‡Department of Applied Chemistry, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan S Supporting Information *
ABSTRACT: (Z)-β-Aryloxyalkenylzincs are synthesized stereoselectively via anti-carbozincation among alkynyl ethers, silyl ketene acetals, and ZnBr2. X-ray analysis revealed the structure of the zinc species is a mononuclear two-coordinate dialkenylzinc that is transformed into functionalized enol ethers as a single isomer in the reaction of various electrophiles.
A
compounds. Herein, we report the regio- and stereoselective anti-carbometalation of alkynyl ethers using ZnBr2 and silyl ketene acetals to synthesize (Z)-β-zincated enol ethers. We recently reported anti-carbometalations of simple alkynes using metal salts and organosilicon nucleophiles.9 In these cases, the metal salt interacts with the alkyne, and then nucleophilic attack of the organosilicon nucleophile to the alkyne occurs at the opposite site of the metal salt to complete the anti-addition. The first step in this study was to survey metal salts in the carbometalation of alkynyl ether 1a with silyl ketene acetal 2a (Table 1). The efficiency of the carbometalation was estimated by the yield of compound 4aa, which was produced by quenching generated alkenylmetal 3 with MeOH. Many typical Lewis acids did not give 4aa at all (entries 1−4). When GaBr3, InBr3, and BiBr3 , which are effective metal salts in our reported carbometalation of simple alkynes,9 were used, carbometalation afforded 4aa in 94%, 96%, and 89% yields, respectively (entries 5−7). ZnBr2, a representative and inexpensive base metal salt, gave the desired product in 82% yield (entry 8). Quenching with MeOD afforded the deuterated product 4aa-d as a single isomer, suggesting that stereo- and regioselective carbozincation occurred to yield β-aryloxyalkenylzinc species 3 (Mt = Zn) (entry 9). Organozincs are more versatile reagents than organogalliums, -indiums, and -bismuths in organic synthesis. This fact prompted us to establish a novel carbozincation. Other zinc halides, ZnCl2 and ZnI2, afforded 4aa in 74% and 78% yields, respectively (entries 10 and 11). Reactions using ZnBr2 at −20 and −30 °C produced better results than reactions at room temperature (entries 12−14). Scheme 2 summarizes the scope of silyl ketene acetal 2. Different types of disubstituted ketene silyl acetals 2b and 2c were applicable to the present carbozincation. Carbozincation using monosubstituted ketene silyl acetals (2d and 2e) also gave the corresponding enol ethers in high yields. The chloride moiety
lkenylmetals are valuable organometallics in organic chemistry.1 In particular, metalated enol ethers are versatile precursors for functionalized enol ethers and carbonyl compounds, which are important building blocks.2 Metalated enol ethers are classified as either α- or β-metalated regioisomers. The lithiation of enol ethers by tert-butyllithium is a useful method to synthesize α-metalated enol ethers.3 On the other hand, the stereo- and regioselective syntheses of β-metalated enol ethers remain challenging. β-Metalated enol ethers are traditionally prepared via a stereospecific halogen−metal exchange (Scheme 1, A).4 However, this protocol has serious Scheme 1. Stereoselective Syntheses of β-Metalated Enol Ethers
problems, including a challenging stereoselective synthesis of the starting β-halo enol ether and the limited number of applicable substrates.5 Recently, carbo- and hydrometalation of alkynyl ethers, which are commercially available or readily prepared, have been leading candidates for the stereoselective syntheses of β-metalated enol ethers (Scheme 1, B). Many carbocuprations and hydroborations in a syn-addition manner already exist.6,7 However, anti-addition reactions to furnish the Z-isomer are limited to hydrostannation with moderate stereoselectivity.8 The anti-carbometalation of alkynyl ethers has never been explored because general carbometalation proceeds via the syn-addition of organometallic © 2017 American Chemical Society
Received: June 17, 2017 Published: July 12, 2017 3927
DOI: 10.1021/acs.orglett.7b01847 Org. Lett. 2017, 19, 3927−3930
Letter
Organic Letters
ether 1d was also applicable to this carbozincation (eq 2). To investigate the influence of the electron density of an alkynyl ether, the intermolecular competitive carbozincation between electron-rich and electron-poor alkynyl ethers was performed (eq 3). The carbozincation of electron-rich alkynyl ether 1b was faster than that of the electron-poor 1c. We characterized the synthesized β-aryloxyalkenylzinc. The reaction among ZnBr2, alkynyl ether 1e, and silyl ketene acetal 2a (eq 4) yielded only one kind of alkenylzinc, which was observed
Table 1. Investigation of Metal Salts in Carbometalation of Alkynyl Ether 1a and Silyl Ketene Acetal 2aa
entry
MtXn
T (°C)
yield (%)
1 2 3 4 5 6 7 8 9c 10 11 12 13 14c
BF3·OEt2 AlCl3 MgBr2 FeCl3 GaBr3 InBr3 BiBr3 ZnBr2 ZnBr2 ZnCl2 ZnI2 ZnBr2 ZnBr2 ZnBr2
rt rt rt rt rt rt rt rt rt rt rt −20 −30 −30
0 0 0 0 94 96 89 82 91 (77% D) 74 78 85 90 (89)d 82d (92% D)
by 1H NMR.10,11 The X-ray structural analysis revealed that the product was bis(β-aryloxyalkenyl)zinc 5ea with Ci symmetry (Figure 1). The trans-geometry between Zn and the substituent
a
MtXn (1 equiv), 1a (1 equiv), 2a (2 equiv), solvent (0.5 M), 2 h. Yields were determined by 1H NMR using 1,1,2,2-tetrachloroethane as an internal standard. cQuenching with MeOD. dIsolated yield. b
Scheme 2. Scope of Silyl Ketene Acetal 2 in Carbozincation of Alkynyl Ether 1aa
Figure 1. X-ray crystal structure of 5ea. Selected bond lengths. Zn−C1 = 1.932(3) Å, Zn−Cipso = 2.914 Å.
derived from 2a showed anti-carbozincation. Surprisingly, the Zn−Cipso contact of 2.914 Å indicated a linear two-coordination geometry of the zinc in 5ea because the Zn and the arene moieties do not interact.12,13 This unusual structure of 5ea is due to the shielding effect of the two perfectly placed aryloxy groups. As far as we could ascertain, this is the first example of a mononuclear two-coordinate dialkenylzinc in the solid state.14 Scheme 3 illustrates a plausible reaction mechanism. The alkyne moiety of alkynyl ether 1 coordinates to ZnBr2.15 Then a
a ZnBr2 (1 equiv), 1 (1 equiv), 2 (2 equiv), Et2O (0.5 M), −20 °C. Isolated yields are shown. bRoom temperature.
Scheme 3. Plausible Mechanism
tolerated the reaction conditions (2f). Phenyl-, thienyl-, and methoxy-substituted silyl ketene acetals (2g, 2h, and 2i) afforded highly functionalized enol ethers. Unsubstituted ketene silyl acetal 2j produced the desired product 4j in 50% yield. The carbozincation of alkynyl aryl ethers bearing either an electron-donating group (1b) or an electron-withdrawing group (1c) at the 4-position of the aryl ring smoothly proceeded to give the corresponding enol ethers in high yields (eq 1). Alkyl alkynyl
nucleophilic attack of silyl ketene acetal 2 regioselectively occurs via an anti-addition to provide (Z)-β-aryloxyalkenylzinc bromide 3 and Me3SiBr (6). The successive carbozincation among 3, 1, and 2 with the same selectivity affords bis(β-aryloxyalkenyl)zinc 5.16 The result shown in eq 3 suggests that the electron-donating group in R1 enhances the coordination ability of the alkyne moiety (A) to accelerate the carbozincation. Many carbozincations of alkynes have been established to date.17 However, most involve transition-metal-catalyzed syn-carbozincation and require an organozinc reagent that is prepared either in advance or in situ. Thus, the reaction reported here is the first example of 3928
DOI: 10.1021/acs.orglett.7b01847 Org. Lett. 2017, 19, 3927−3930
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Organic Letters
corresponding products (8n, 8o, 8p, and 8q). Heteroaryl halides were also suitable for this sequential process (8r, 8s, and 8t). Enol ethers 8 produced via the carbozincation/Negishi coupling sequential process were applied to the synthesis of indole- and benzofuran-2-acetic ester derivatives, which are a very important class of biological active heterocyclic molecules.21 Reduction of the nitro group of enol ether 8o followed by intramolecular cyclization between arylamine and enol ether moieties furnished indole derivative 9 (eq 5).6b Treatment of enol ether 8n with 4 M HCl in a 1,4-dioxane solution yielded benzofuran derivative 10 (eq 6).6b
carbozincation using an inorganic zinc salt that directly interacts with an alkyne.18−20 We examined Negishi coupling using the formed βaryloxyalkenylzinc (Scheme 4).9 After the carbozincation of 1a Scheme 4. Scope of Silyl Ketene Acetals 2 in One-Pot Carbozincation/Negishi Coupling Processa
Further applications of the β-aryloxyalkenylzinc were investigated (Scheme 6). The addition reaction of β-
a
ZnBr2 (1.1 equiv), 1a (1.1 equiv), 2 (2.2 equiv), 7a (1 equiv), Pd(PPh 3 ) 4 (5.5 mol %). Isolated yields are shown. b The carbozincation was conducted at room temperature.
Scheme 6. Stereo- and Regioselective Synthesis of Complex Enol Ethers via Carbozincation
with ZnBr2 and 2a, 4-iodotoluene 7a, a catalytic amount of Pd(PPh3)4, and THF were added to the reaction mixture. Coupling proceeded to give the p-tolyl-substituted enol ether 8a in 81% yield with retention of the stereochemistry of the alkene moiety. Therefore, a series of silyl ketene acetals 2 were tested. Dialkyl- and monoalkyl-substituted ketene silyl acetals were feasible substrates that produced moderate to high yields (8c, 8d, 8e, and 8f). Aryl- and heteroaryl-substituted ones also afforded the corresponding products (8g and 8h). Many aryl iodides 7 were applicable to the carbozincation/ Negishi coupling process (Scheme 5). The coupling using either
aryloxyalkenyl zinc to aldehyde 11 occurred in a one-pot manner.7,9 The Cu-mediated substitution reaction of allylic bromide 13 gave skipped diene 14 in 43% yield.9 The treatment of I2 afforded the corresponding iodinated enol ether 15. These different sequential reactions proceeded without a loss of the stereochemistry of the zincated enol ether to give the corresponding enol ethers. These results demonstrate that this is powerful tool to synthesize refined enol ethers in organic synthesis. In summary, we established the anti-carbozincation of alkynyl ethers using ZnBr2 and silyl ketene acetals to give (Z)-β-zincated enol ethers stereo- and regioselectively. The zincated enol ethers are applicable to many organic transformation to complete the stereoselective synthesis of complex enol ethers.
Scheme 5. Scope of Aryl Iodides 7 in Carbozincation/Negishi Coupling Process
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a
ZnBr2 (1.1 equiv), 1a (1.1 equiv), 2a (2.2 equiv), 7 (1 equiv), Pd(PPh 3 ) 4 (5.5 mol %). Isolated yields are shown. b The carbozincation was conducted at −30 °C. cArBr was used instead of ArI.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b01847. Experimental procedures, characterization of products, and spectroscopic data (PDF) Crystallographic data for 5ea (CIF)
electron-rich or electron-poor aryl iodides smoothly produced the desired products (8i, 8j, and 8l). Ester moieties were compatible with the produced alkenylzinc (8k and 8m). The coupling reaction of β-aryloxyalkenylzinc with many types of ortho-substituted aryl iodides such as methyl-, methoxymethyl-, nitro-, and phthaloyl-substituted ones smoothly gave the
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. 3929
DOI: 10.1021/acs.orglett.7b01847 Org. Lett. 2017, 19, 3927−3930
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[email protected].
(9) (a) Nishimoto, Y.; Moritoh, R.; Yasuda, M.; Baba, A. Angew. Chem., Int. Ed. 2009, 48, 4577. (b) Nishimoto, Y.; Ueda, H.; Yasuda, M.; Baba, A. Chem. - Eur. J. 2011, 17, 11135. (c) Nishimoto, Y.; Takeuchi, M.; Yasuda, M.; Baba, A. Angew. Chem., Int. Ed. 2012, 51, 1051. (10) The reaction between ZnBr2 (1 equiv), alkynyl ether 1e (1 equiv), and silyl ketene acetal 2a (2 equiv) gave different signals from those of dialkenylzinc 5ea. The spectra showed the mixture of monoalkenyl- and dialkenylzinc compounds, which indicated that the fast exchange of alkenyl groups between monoalkenyl- and dialkenylzincs would occur. We ar enow investigating this phenomenon in detail. Thus, we could not isolate a monoalkenylzinc species. (11) See the Supporting Information for the experimental procedure. (12) Zn complexes including the interaction between Zn and arene: (a) Gutschank, B.; Bayram, M.; Schulz, S.; Bläser, D.; Wölper, C. Eur. J. Inorg. Chem. 2013, 2013, 5495. (b) Schmidt, S.; Schulz, S.; Bläser, D.; Boese, R.; Bolte, M. Organometallics 2010, 29, 6097. (c) Wehmschulte, R. J.; Wojtas, L. Inorg. Chem. 2011, 50, 11300. (d) Guerrero, A.; Martin, E.; Hughes, D. L.; Kaltsoyannis, N.; Bochmann, M. Organometallics 2006, 25, 3311. (13) The Zn and Cipso contact of 2.914 Å in complex 3ea is longer than the distance between Zn and C of the arene in reported Zn−arene complexes. Zn and ipso-C do not interact in the case of zinc(II) dithiolate involving the Zn and ipso-C contact of 2.80 Å. (a) Nguyen, T.; Panda, A.; Olmstead, M. M.; Richards, A. F.; Stender, M.; Brynda, M.; Power, P. P. J. Am. Chem. Soc. 2005, 127, 8545. (b) Blundell, T. J.; Hastings, F. R.; Gridley, B. M.; Moxey, G. J.; Lewis, W.; Blake, A. J.; Kays, D. L. Dalton Trans. 2014, 43, 14257. (14) (a) Zhou, Y.; Zhang, W.-X.; Xi, Z. Organometallics 2012, 31, 5546. (b) Zhao, X.; Lough, A. J.; Stephan, D. W. Chem. - Eur. J. 2011, 17, 6731. (15) Wilson, E. E.; Oliver, A. G.; Hughes, R. P.; Ashfeld, B. L. Organometallics 2011, 30, 5214. (16) When 2 equiv of an alkynyl ether and 1 equiv of ZnBr2 were used, the enol ether product was obtained in 168% yield based on ZnBr2 (see the Supporting Information). (17) (a) Nolan, S. P.; Navarro, O. C−C Bond Formation by Crosscoupling. In Comprehensive Organometallic Chemistry, 3rd ed.; Crabtree, R. H., Mingos, D. M. P., Eds.; Elsevier: Amsterdam, 2007; Vol. 11, pp 1− 37. (b) Knochel, P.; Perrone, S.; Grenouillat, N. Zinc and Cadmium. In Comprehensive Organometallic Chemistry, 3rd ed.; Crabtree, R. H., Mingos, D. M. P., Eds.; Elsevier: Amsterdam, 2007; Vol. 9, pp 81−143. (c) Sklute, G.; Cavender, H.; Marek, I. Carbozincation Reactions of Carbon−Carbon Multiple Bonds. In Organic Reactions; Denmark, S. E., Ed.; John Wiley & Sons, Inc.: Hoboken, 2015; Vol. 87, pp 1−258. (18) Carboxyzincation of alkynes using zinc metal: Nogi, K.; Fujihara, T.; Terao, J.; Tsuji, Y. J. Am. Chem. Soc. 2016, 138, 5547. (19) An anti-carbozincation of alkynes is limited to Fe-catalyzed reductive carbozincation using zinc metal and radical carbozincation of acetylenedicarboxylates. (a) Cheung, C. W.; Zhurkin, F. E.; Hu, X. J. Am. Chem. Soc. 2015, 137, 4932. (b) Cheung, C. W.; Hu, X. Chem. - Eur. J. 2015, 21, 18439. (c) Maury, J.; Feray, L.; Bertrand, M. P. Org. Lett. 2011, 13, 1884. (20) There is a report for the intramolecular carbozincation of an active methylene compound having an alkyne moiety by ZnCl2−Et3N. However, a zinc enolate would be formed in situ, and it was unclear whether the carbozincation occurred via an anti or syn addition mechanism. Kitagawa, O.; Suzuki, T.; Inoue, T.; Taguchi, T. Tetrahedron Lett. 1998, 39, 7357. (21) For selected reports, see: (a) Nagahara, T.; Yokoyama, Y.; Inamura, K.; Katakura, S.; Komoriya, S.; Yamaguchi, H.; Hara, T.; Iwamoto, M. J. Med. Chem. 1994, 37, 1200. (b) Pearce, A. N.; Babcock, R. C.; Battershill, C. N.; Lambert, G.; Copp, B. R. J. Org. Chem. 2001, 66, 8257.
ORCID
Makoto Yasuda: 0000-0002-6618-2893 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by JSPS KAKENHI Grant Nos. JP15H05848 in Middle Molecular Strategy and JP16K05719. Part of the work was supported by the Sumitomo Electric Industries Group CSR Foundation to M.Y. Y.N. acknowledges support from the Frontier Research Base for Global Young Researchers, Osaka University, of the MEXT program and from the Mitsui Chemicals Award in Synthetic Organic Chemistry. We recognize the Analytical Instrumentation Facility, Graduate School of Engineering, Osaka University, for the assistance in obtaining the MS spectra.
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