Anti-Carboalumination of Alkynes Using Aluminum Trihalide and Silyl

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

pubs.acs.org/OrgLett

Anti-Carboalumination of Alkynes Using Aluminum Trihalide and Silyl Ketene Imines: Stereo- and Regioselective Synthesis of Alkenylaluminum Compounds Bearing a Cyano Group Yoshihiro Nishimoto,*,† Rina Hirase,‡ and Makoto Yasuda*,‡ †

Frontier Research Base for Global Young Researchers, Center for Open Innovation Research and Education (COiRE), Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan ‡ Department of Applied Chemistry, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan S Supporting Information *

ABSTRACT: An organoaluminum-free and catalyst-free anti-carboalumination of alkynes using aluminum trihalides and silyl ketene imines was developed. Three components, an alkyne, AlX3, and a silyl ketene imine, were simply mixed to give the alkenylaluminum bearing a cyano group with regioselectivity. Theoretical calculations revealed the effective activation of the alkyne by AlX3 to enhance the regioselective carboalumination. The synthesized alkenylaluminums were applicable to many organic transformations.

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arboalumination is a significant carbometalation reaction because aluminum is an abundant, inexpensive, and environmentally benign base metal. In particular, the carboalumination of alkynes has played an important role in industrial and pharmaceutical chemistry as well as in the total synthesis of natural products because of the versatile utility of alkenylaluminums.1−3 However, two serious problems persist in this field (Figure 1A). One is that most of the established reactions are limited to syn-addition to alkynes. This limitation arises from the use of combinations of transition metal catalysts

and organoaluminum reagents (Figure 1A, Problem 1). For anti-carboalumination, only two methods have been developed. An anti-carboalumination using R3Al/R2Mg bimetallic species was reported,4 but only silylated 1,3-enynes and a phenylethynylsilane were applicable. Yamamoto developed an anticarboalumination using EtAlCl2 and silyl enol ethers.5 However, this reaction was limited to intramolecular mechanisms, and the desired alkenylaluminum was isomerized. Another serious problem is the need for organoaluminum reagents, the lack of which has critically narrowed the scope of carbon nucleophiles (R1) (Figure 1A, Problem 2). Suitable carbon nucleophiles are limited to simple alkyl-, alkenyl-, and arylaluminums, and the above-mentioned carboalumination reported by Yamamoto is the only example involving enolate nucleophiles.5 Herein we report an organoaluminum-free, catalyst-free, intermolecular anti-carboalumination of alkynes using an aluminum trihalide and silyl ketene imines6 (Figure 1B). As far as we can ascertain, this is the first example of carboalumination using inorganic aluminum salts (Figure 1B, Advantage 1). The application of silyl ketene imines provides functionalized alkenylaluminum species bearing a cyano group, which give various β,γ-unsaturated nitriles via sequential transformations (Figure 1B, Advantage 2). We recently studied carbometalations of alkynes using silyl ketene acetals and main-group metal salts.7 These carbometalations occurred through the anti-addition mechanism shown in Figure 1B. This is a useful methodology for the regio- and stereoselective synthesis of functionalized alkenylmetals bearing an ester moiety. However, only rare metal salts, such as

Figure 1. Carboalumination of alkynes.

Received: May 7, 2018

© XXXX American Chemical Society

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DOI: 10.1021/acs.orglett.8b01371 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters InBr3,7a,b GaBr3,7c and BiBr3,7d,e are effective with simple alkynes, although a Zn salt7f can be used in the carbometalation of highly reactive alkynyl ethers. Therefore, we endeavored to employ aluminum salts and make this methodology more versatile, low-cost, and environmentally benign. First, organosilicon nucleophiles were investigated in the reaction of phenylacetylene (1a) using AlCl3 (see Scheme S1 in the Supporting Information). However, the reaction using silyl ketene acetal did not proceed, unlike those using InBr3, GaBr3, and BiBr3, because the strong coordination of an oxygen atom deactivated AlCl3. Noncoordinating organosilicons such as phenyl-, allyl-, and alkynylsilanes gave complicated products. To our delight, silyl ketene imine (SKI) 2a, which is used as an α-cyanoalkyl anion equivalent,6 afforded the addition product 4aa in 72% yield (Table 1, entry 1). The yield of the

Scheme 1. Scope and Limitations of Alkynes 1 and Silyl Ketene Imines 2a

Table 1. Optimization of Conditions for Carboalumination of 1a with 2aa

entry

MtX

solvent

yield of 4aa (%)b

1 2 3 4 5 6 7 8 9 10

AlCl3 AlBr3 AlI3 AlBr3 Al(OTf)3 EtAlCl2 Et2AlCl GaBr3 InBr3 AlBr3

CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 toluene

72 76 69 78c 0 27 0 49 48 74

a 1 (0.5 mmol), AlBr3 (0.75 mmol), 2 (0.75 mmol), CH2Cl2 (1 mL). Isolated yields are shown. bThe structure of 5ac was determined by Xray diffraction analysis. cA 1 M HCl solution was used in place of ICl. d NBS was used in place of ICl.

a

1a (0.5 mmol), MtX (0.75 mmol), 2a (0.75 mmol), solvent (1 mL). Yields were determined by 1H NMR analysis. cQuenched with MeOD. The deuterated product 4aa-d (96% D) was obtained.

b

The stereoselectivity of iodination was perfectly controlled. Other α-alkyl-α-aryl-substituted SKIs also gave the products 5ab and 5ac in 86% and 57% yield, respectively. α,α-Diphenylsubstituted SKI also gave the corresponding product 5ad. Electron-rich aryl-substituted SKIs afforded moderate yields (5ae and 5af), although the reaction using an electron-deficient aryl-substituted SKI resulted in a 21% yield (5ag). SKIs bearing meta-substituted aryl groups were applicable to this reaction (5ah and 5ai). Thienyl-substituted SKI underwent carboalumination to give the product 4aj.10 The use of NBS instead of ICl smoothly gave alkenyl bromide 6 in 86% yield. Various alkynes were applicable to this sequential process. Para-substituted aromatic alkynes bearing electron-withdrawing or electrondonating groups gave the corresponding alkenyl iodides in high yields (5ba, 5ca, 5da, and 5ea), although the nitro group was not suitable (5fa). The carboalumination of meta-substituted aromatic alkynes proceeded smoothly (5ga and 5ha). The carboalumination of the alkyne moiety of an enyne occurred selectively to give 1,3-diene product 5ia in 50% yield. In contrast to aromatic alkynes, aliphatic alkynes and internal alkynes were not applicable to the present carboalumination. The intermolecular competitive carboalumination between pMeO- and p-Cl-substituted aromatic alkynes (1e and 1c) was carried out to investigate the influence of the alkyne electron density. Electron-rich alkyne 1e underwent carboalumination more readily than electron-deficient alkyne 1c.11

corresponding addition product after quenching with H2O revealed the efficiency of the carboalumination. It was surprising that this carboalumination proceeded using a simple and common aluminum salt without any catalyst. AlBr3 and AlI3 also gave product 4aa in 76% and 69% yield, respectively (entries 2 and 3). Quenching with MeOD afforded the deuterated product 4aa-d as a single isomer, and the D atom was introduced exclusively cis to the Ph group (entry 4), suggesting that the regioselective anti-carboalumination proceeded to afford alkenylaluminum product 3 (Mt = Al). Al(OTf)3 was not effective (entry 5). EtAlCl2 and Et2AlCl, which were suitable for intramolecular carboalumination using silyl enol ethers,5 resulted in a low yield and no reaction, respectively (entries 6 and 7).8 It should be noted that AlBr3 was superior to GaBr3 and InBr3 in this carbometalation (entries 8 and 9).8 Toluene was also a suitable solvent (entry 10). The scope of alkynes and SKIs in the carboalumination was surveyed (Scheme 1). In this case, iodination of the synthesized alkenylaluminum using ICl was carried out to obtain the corresponding alkenyl iodide. After carboalumination using AlBr3, 1a, and 2a under the conditions listed in entry 2 of Table 1, treatment with ICl gave alkenyl iodide 5aa in 83% yield.9 B


Letter

Organic Letters A theoretical calculation analysis of the activation of alkyne 1a by MtBr3 was performed (Table 2). The optimized

Scheme 2. Plausible Reaction Mechanism

Table 2. Comparison of Parameters Describing Activation of Alkyne 1a by Metal Saltsa

MtBr3

ΔH (kcal/mol)

ΔX/X1 (%)b

θ (deg)

eigenvalue (eV)c

charge of C2 d

AlBr3 GaBr3 InBr3

−5.23 −2.40 −6.11

1.85 1.57 1.27

150.6 155.2 160.2

−3.40 −3.31 −3.16

+0.189 +0.163 +0.120

between the vinylic hydrogen (H1) and the Ph(NC)(Me)C substituent. The results of the intermolecular competitive carboalumination suggest that the electron-donating group delocalizes to a positive charge generated on the alkyne moiety in transition state 7 to accelerate the carboalumination. Pd-catalyzed cross-coupling using alkenylaluminums is an effective method for installing alkenyl units.1,2 Therefore, the synthesized alkenylaluminums were applied to the crosscoupling reaction with acid clorides (Scheme 3). After the

B3LYP/6-31+G(d,p) for H, C, DGDZVP for Al, Ga, In, Br. bΔX = X2 − X1. cFor the LUMO of the MtBr3·1a complex. dAs determined by NBO analysis. a

Scheme 3. Pd-Catalyzed Cross-Coupling of Alkenylaluminum 3 with Acid Chlorides 8a

structures of the MtBr3·1a complex (Mt = Al, Ga, and In) showed that a Mt atom interacted with the terminal carbon (C1) of the alkyne moiety rather than the internal carbon (C2). Alkyne 1a exothermically associated with AlBr3 (ΔH = −5.23 kcal/mol). The carbon−carbon triple bond was elongated (ΔX/X1 = 1.85%) via complexation with AlBr3, and a natural bond orbital (NBO) analysis showed that the positive charge on the internal carbon (C2) increased and the CC bond became more polarized. The alkyne configuration deviated from linearity (∠C2−C1−H = 180° → 150.6°) after complexation, indicating that the effective bonding interaction between the C1 and Al atoms led to a change from sp to sp2 hybridization at the C1 atom. The LUMO of AlBr3·1a mainly consisted of the π* orbital of the alkyne moiety, a vacant p orbital of the Al atom, and the Ψ2 orbital of the benzene ring (see Scheme S3). This LUMO was localized around the alkyne moiety, unlike the LUMO of 1a. The energy of the LUMO of AlBr3·1a (−3.40 eV) was lower than that of the LUMO of 1a (−1.24 eV). These results reveal that AlBr3 sufficiently activated alkyne 1a to enhance the regioselective nucleophilic addition of SKI 2 to the C2 atom. Next, five parameters of MtBr3 were compared: the complexation energy (ΔH), elongation of the carbon−carbon triple bond (ΔX/X1), deviation of ∠C2−C1−H (θ) from linearity, LUMO energy (eigenvalue), and the positive charge on C2 (see Table S1 for other parameters). The complexation energies (ΔH) indicated that InBr3 favored complex formation with alkyne 1a; however, the other four parameters indicated that activation of alkyne 1a by AlBr3 was the most effective. These results are consistent with the fact that AlBr3 gave a better result than GaBr3 or InBr3 in the carbometalation of 1a using SKI 2a (Table 1, entries 2, 8, and 9). The atomic radius of aluminum rather than gallium or indium is closer to the atomic radius of carbon, so AlBr3 could most effectively activate the alkyne via a σ-bonding interaction between the Al and C1 atoms.12 Scheme 2 illustrates a plausible reaction mechanism. First, alkyne 1 coordinates to AlBr3. The positive charge then increases at the internal carbon of alkyne 1.13,14 Next, nucleophilic attack of SKI 2 regio- and stereoselectively occurs via an anti addition (7) to provide alkenylaluminum 3 and tBuMe2SiBr. We successfully isolated and characterized alkenylaluminum 3ab by NMR spectroscopy.15 The observed nuclear Overhauser effect between the vinylic hydrogen (H1) and the methyl group (CH23) verified the cis arrangement

a

1a (0.5 mmol), AlBr3 (0.75 mmol), 2 (0.75 mmol), CH2Cl2 (1 mL), 8 (1 mmol), 9 (0.015 mmol), 1,4-dioxane (2 mL). Isolated yields are shown. bThe structure of 10e was determined by X-ray diffraction analysis.

carboalumination of alkyne 1a using AlBr3 and SKI 2a, propionyl chloride (8a), palladium catalyst (9), and 1,4-dioxane were added to the reaction mixture. The coupling of alkenylaluminum 3 with 8a proceeded to give enone 10a in 54% yield. Sterically hindered acid chlorides were applicable to this cross-coupling (10b and 10c). Aromatic acid chlorides also afforded high yields (10d−i). In all cases, β-disubstituted enones were stereoselectively obtained with retention of the double-bond configuration. On the other hand, the Pdcatalyzed coupling using aryl iodides resulted in no reaction or low yields. The addition reaction of alkenylaluminum 3 to unsaturated bonds proceeded successfully. The addition of 3ad to the nitrogen−nitrogen double bond of diisopropyl azodicarboxylate (11) afforded alkenylhydrazine 12 in 78% yield (Scheme 4A).15 C


Letter

Organic Letters ORCID

Scheme 4. Sequential Organic Synthesis Processes Involving Carboalumination

Yoshihiro Nishimoto: 0000-0002-7182-0503 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 Grants JP15H05848 in Middle Molecular Strategy, JP16K05719, and 18H01977. Y.N. acknowledges support from the Frontier Research Base for Global Young Researchers, Osaka University, of the MEXT Program. M.Y. acknowledges financial support from the Mitsui Chemicals Award in Synthetic Organic Chemistry and the Shorai Foundation for Science and Technology to Y.N.

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a

The structures of 12 and 15 were determined by X-ray diffraction analysis.

Unexpectedly, during the addition reaction to aldehyde 13, the sequential intramolecular Friedel−Crafts alkylation of addition product 14 afforded indene 15 in a moderate yield (Scheme 4B).16 Brominated β,γ-unsaturated nitrile 6 was treated with NaBH4, followed by iBu2AlH, to provide functionalized amine 16 (Scheme 4C). It should be noted that these transformations provided the products while retaining the stereochemistry of the alkene moiety of alkenylaluminum 3.17 In conclusion, we have developed a regioselective anticarboalumination of alkynes using AlBr3 and silyl ketene imines to give alkenylaluminums bearing a cyano group. DFT calculation analysis revealed that AlBr3 could more effectively activate the alkyne than GaBr3 and InBr3 could. The synthesized alkenylaluminums were applicable to many types of organic transformations to give β,γ-unsaturated nitriles.

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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.8b01371. Experimental procedures, characterization of products, and spectroscopic data (PDF) Accession Codes

CCDC 1837981−1837982, 1838085, and 1838150 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/ data_request/cif, or by e-mailing [email protected]. uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.

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REFERENCES

(1) See selected reviews of carboalumination: (a) Dzhemilev, U. M.; D’yakonov, V. A. In Modern Organoaluminum Reagents: Preparation, Structures, Reactivity and Use; Woodward, S., Dagorne, S., Eds.; Springer: Berlin, 2013; pp 215−244. (b) Xu, S.; Negishi, E.-I. Acc. Chem. Res. 2016, 49, 2158. (c) Knochel, P. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, U.K., 1991; Vol. 4, pp 865−912. (d) Huo, S. Carboalumination Reactions. In Patai’s Chemistry of Functional Groups; Rappoport, Z., Liebman, J. F., Marek, I., Eds.; John Wiley and Sons: Hoboken, NJ, 2016; pp 1−64. (2) For selected reviews of the utilization of organoaluminums in organic synthesis, see: (a) Negishi, E.-I. Bull. Chem. Soc. Jpn. 2007, 80, 233. (b) Negishi, E.-I.; Wang, G.; Rao, H.; Xu, Z. J. Org. Chem. 2010, 75, 3151. (c) Saito, S. In Comprehensive Organometallic Chemistry, 3rd ed.; Crabtree, R. H., Mingos, D. M. P., Eds.; Elsevier: Amsterdam, 2007, Vol. 9, pp 245−296. (d) Negishi, E.-I.; Huang, Z.; Wang, G.; Mohan, S.; Wang, C.; Hattori, H. Acc. Chem. Res. 2008, 41, 1474. (e) Modern Organoaluminum Reagents: Preparation, Structures, Reactivity and Use; Woodward, S., Dagorne, S., Eds.; Springer: Berlin, 2013. (3) For recent reports of the use of alkenylaluminums in organic synthesis, see: (a) Lipshutz, B. H.; Amorelli, B. J. Am. Chem. Soc. 2009, 131, 1396. (b) Lipshutz, B. H.; Butler, T.; Lower, A.; Servesko, J. Org. Lett. 2007, 9, 3737. (c) Kawamura, S.; Agata, R.; Nakamura, M. Org. Chem. Front. 2015, 2, 1053. (d) Willcox, D.; Woodward, S.; Alexakis, A. Chem. Commun. 2014, 50, 1655. (e) Wipf, P.; Waller, D. L.; Reeves, J. T. J. Org. Chem. 2005, 70, 8096. (f) Tang, W.; Liu, S.; Degen, D.; Ebright, R. H.; Prusov, E. V. Chem. - Eur. J. 2014, 20, 12310. (g) Lamariano-Merketegi, J.; Lorente, A.; Gil, A.; Albericio, F.; Alvarez, M. Eur. J. Org. Chem. 2015, 2015, 235. (4) Hayami, H.; Oshima, K.; Nozaki, H. Tetrahedron Lett. 1984, 25, 4433. (5) (a) Imamura, K.-I.; Yoshikawa, E.; Gevorgyan, V.; Yamamoto, Y. Tetrahedron Lett. 1999, 40, 4081. (b) Imamura, K.-I.; Yoshikawa, E.; Gevorgyan, V.; Sudo, T.; Asao, N.; Yamamoto, Y. Can. J. Chem. 2001, 79, 1624. (6) For a review of reactions using silyl ketene imines, see: (a) Denmark, S. E.; Wilson, T. W. Angew. Chem., Int. Ed. 2012, 51, 9980. (b) Lu, P.; Wang, Y. Chem. Soc. Rev. 2012, 41, 5687. For recent reports, see: (c) Zhao, J.; Liu, X.; Luo, W.; Xie, M.; Lin, L.; Feng, X. Angew. Chem., Int. Ed. 2013, 52, 3473. (d) Denmark, S. E.; Wilson, T. W.; Burk, M. T. Chem. - Eur. J. 2014, 20, 9268. (7) (a) Nishimoto, Y.; Moritoh, R.; Yasuda, M.; Baba, A. Angew. Chem., Int. Ed. 2009, 48, 4577. (b) Nishimoto, Y.; Ueda, H.; Inamoto, Y.; Yasuda, M.; Baba, A. Org. Lett. 2010, 12, 3390. (c) Nishimoto, Y.; Ueda, H.; Yasuda, M.; Baba, A. Chem. - Eur. J. 2011, 17, 11135. (d) Nishimoto, Y.; Takeuchi, M.; Yasuda, M.; Baba, A. Angew. Chem., Int. Ed. 2012, 51, 1051. (e) Nishimoto, Y.; Takeuchi, M.; Yasuda, M.;

AUTHOR INFORMATION

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Organic Letters Baba, A. Chem. - Eur. J. 2013, 19, 14411. (f) Nishimoto, Y.; Kang, K.; Yasuda, M. Org. Lett. 2017, 19, 3927. (8) In entries 5−9, the recovery of alkyne 1a was low (0% to ca. 30%), probably because some side reactions such as polymerization of 1a occurred. (9) For halogenation of alkenylaluminums while retaining the stereochemistry of the alkene moiety, see: (a) Crombie, L.; Hobbs, A. J. W.; Horsham, M. A.; Blade, R. J. Tetrahedron Lett. 1987, 28, 4875. (b) Kiehl, A.; Eberhardt, A.; Müllen, K. Liebigs Ann. 1995, 1995, 223. (c) Romo, D.; Rzasa, R. M.; Shea, H. A.; Park, K.; Langenhan, J. M.; Sun, L.; Akhiezer, A.; Liu, J. O. J. Am. Chem. Soc. 1998, 120, 12237. (d) Shakhmaev, R. N.; Ishbaeva, A. U.; Zorin, V. V. Russ. J. Org. Chem. 2012, 48, 908. (e) Müller, D.; Alexakis, A. Chem. - Eur. J. 2013, 19, 15226. (f) Anantoju, K. K.; Mohd, B. S.; Maringanti, T. C. Tetrahedron Lett. 2017, 58, 1499. (10) Quenching with ICl promoted iodination of a thiophene moiety of the corresponding product. (11) See Scheme S2 for a detailed description of the experiment. (12) In general, the C−Al bond energy exceeds the C−Ga and C−In bond energies. See: The Group 13 Metals Aluminium, Gallium, Indium and Thallium; Aldridge, S., Downs, A. J., Eds.; John Wiley and Sons: Hoboken, NJ, 2011. (13) For the interaction between an aluminum(III) center and the triple bond of an alkyne, see: Stucky, G. D.; McPherson, A. M.; Rhine, W. E.; Eisch, J. J.; Considine, J. L. J. Am. Chem. Soc. 1974, 96, 1941. (14) For reports of catalytic reactions involving the carboalumination of alkynes, see: (a) Yoshikawa, E.; Gevorgyan, V.; Asao, N.; Yamamoto, Y. J. Am. Chem. Soc. 1997, 119, 6781. (b) Matsukawa, Y.; Asao, N.; Kitahara, H.; Yamamoto, Y. Tetrahedron 1999, 55, 3779. (c) Asao, N.; Shimada, T.; Yamamoto, Y. J. Am. Chem. Soc. 1999, 121, 3797. (d) Asao, N.; Yamamoto, Y. Bull. Chem. Soc. Jpn. 2000, 73, 1071. (e) Yoshikawa, E.; Kasahara, M.; Asao, N.; Yamamoto, Y. Tetrahedron Lett. 2000, 41, 4499. (f) Asao, N.; Shimada, T.; Shimada, T.; Yamamoto, Y. J. Am. Chem. Soc. 2001, 123, 10899. (15) See the Supporting Information for a detailed description of the experimental procedure. The alkenylaluminum could not be characterized by X-ray diffraction analysis because of its poor stability. (16) DeBergh, J. R.; Spivey, K. M.; Ready, J. M. J. Am. Chem. Soc. 2008, 130, 7828. (17) A plausible reaction mechanism is provided in the Supporting Information.

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Anti-Carboalumination of Alkynes Using Aluminum Trihalide and Silyl

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