Norbornene-Catalyzed ortho Aliphatic Acylation with Mixed

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

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Palladium/Norbornene-Catalyzed ortho Aliphatic Acylation with Mixed Anhydride: Selectivity and Reactivity Shibo Xu,† Julong Jiang,† Linlin Ding, Yao Fu,* and Zhenhua Gu* Department of Chemistry and Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui 230026, P. R. China S Supporting Information *

ABSTRACT: A palladium/norbornene-catalyzed ortho acylation for the efficient synthesis of functionalized alkyl aryl ketones is reported. Studies on the electronic and steric properties of mixed aryl anhydrides indicated that the cross-coupling favored with the electron-enriched aryl acyl group. DFT calculation on the oxidative addition of Pd(II) with 2,4,6-(Cl)3C6H2CO2C(O)Ph suggested that 2,4,6-(Cl)3C6H2C(O)−O bond cleavage was more kinetically disfavored than that of the PhC(O)−O bond by 11.7 kJ/mol. Scheme 1. Pd/NBE-Catalyzed ortho Acylation

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etones are one of the most important functional groups in organic chemistry and material science. They widely exist in bioactive natural products and pharmaceutical molecules, such as methadone, raloxifene, and (−)-steganone1 (Figure 1).

Figure 1. Ketone-containing bioactive molecules.

Ketones are also fundamental building blocks in organic synthesis, which could be diversely transformed into alkenes, alcohols, amines, oximes, etc. For the synthesis of ketones, the classic methods include Friedel−Crafts acylation, Weinreb amide protocol, and the oxidation of secondary alcohols. However, the use of excess Lewis/Brønsted acid, along with the poor regioselectivity observed for the products, significantly restricts the application of Friedel−Crafts acylation. Recently, transition-metal-catalyzed ketone synthesis has caught growing attention, as it provides alternative ways for the construction of these compounds, and some typical contributors include Yamamoto,2 Gooßen,3 Liebeskind and Srogl,4 Gong,5 and Wu and Cui.6 Palladium/norbornene (NBE)-catalyzed ortho functionalization of aryl halides, which includes alkylation, arylation, amination, and chlorination, represents a powerful method for the construction of polyfunctionalized aromatic compounds, to which the most significant contributions are from the groups of Catellani and Lautens.7−13 Recently, Liang, Dong, and our groups independently developed a protocol for the orthoacylation of aryl halides.14 This method provided an efficient way for regiospecific construction of aryl ketones under mild conditions (Scheme 1a). However, there are remaining challenges yet to be solved. First, the reaction worked well © XXXX American Chemical Society

with aromatic acyl chlorides or anhydrides, while poor yields were obtained for aliphatic acid derivatives with 5 mol % of palladium, particularly for α-nonbranched aliphatic acid derivatives. Second, the synthesis of acid anhydride would consume two molecules of carboxylic acid, in which one of them was actually discarded as waste in the acylation reaction (see Scheme 1a). Considering the difficulties encountered in the multistep synthesis of these complex carboxylic acids, as well as the atom efficiency, the call for an alternative strategy is therefore urgent. The formation of ketenes from the facile elimination of α-nonbranched aliphatic acyl chloride or anhydride might account for the low yields of the corresponding desired products. More recently, Dong and coworkers introduced an alkoxycarbonyl group to various Received: November 13, 2017

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DOI: 10.1021/acs.orglett.7b03514 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters aromatic rings by selectively cleaving a C(O)O−C(O)OR bond, where both steric and electronic properties of the mixed anhydride are believed to play vital roles.15 Given the importance of aryl alkyl ketones, herein we report our efforts made for the introduction of aliphatic carbonyl groups to the ortho position of aryl iodides, where mixed anhydrides from 2,4,6-trichlorobenzoyl chloride showed remarkable reactivity and selectivity (Scheme 1b). Our primary goal was to find a proper activation reagent that could activate the aliphatic acid while the activation reagent itself would not act as an acylation reagent (Scheme 2). The Scheme 2. Electronic Effect

Figure 2. (a) Correlation between the reaction rate and the loading of palladium catalyst. (b) Optimized charge distributions on TS1a and TS1b.

Scheme 3. Energy Profile of the Pathway Leading to the Major Product Prod1a

reaction with mixed anhydride from benzoic acid and 2,6dimethoxybenzoyl chloride gave a mixture of biaryl ketones 2 and 3a with a ratio of 1:6.6. It indicated that the reaction favored coupling with the electron-enriched aryl acyl group. In other words, the selectivity depended more on the electronic property rather than steric effects. The reaction of pfluorobenzoyl chloride gave a 1:1 mixture of 2:3b, while the one with 2-chlorobenzoyl chloride offered a 2:1 mixture favoring the formation of the desired product 2. The use of 2,6-dichlorobenzoyl chloride or Yamaguchi reagent (2,4,6trichlorobenzoyl chloride) could further improve the selectivity on the product 2. A complicated mixture was detected when 4nitrobenzoyl chloride was used. To gain more insight into the selectivity, DFT calculations were performed with the B3LYP hybrid functional,16 which was corrected with empirical dispersion term (Grimme-D3).17 Kinetic experimental studies by using benzoic anhydride and N-methyl-N-tosyl-4-iodo-3-methylaniline as the model compounds found that the reaction rate had a first-order dependence on the concentration of PdCl2 (Figure 2a) (see Supporting Information for details). These results suggested that the reaction preferred to proceed via a palladium monomer species rather than a bimetallic pathway.18 Thus, our theoretical study focused on the Pd(0)−Pd(II)−Pd(IV) process. It was found that the Pd(IV) is more satisfied with the six-coordinate pattern and adopts an octahedral geometry. Carboxylate acts as a bidentate ligand to bind with the Pd(IV) atom in Int1a and Int1b (Schemes 3 and 4), and the maps the ESP charge distributions on the transition states were shown in Figure 2b. This bidentate model might also account for our previous observation that acid anhydrides showed a high reactivity while acyl chlorides were inert under the identical conditions. The intermediate Int4 is more stable than Int5 by 10.3 kJ/mol, indicating Int4 is the thermodynamically controlled product.

Scheme 4. Energy Profile of the Pathway Leading to the Side Product Prod1b

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DOI: 10.1021/acs.orglett.7b03514 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 5. Substrate Scopea

Shown in Schemes 3 and 4 are the detailed mechanism of the oxidative addition and the subsequent reductive elimination. Since all of the transition states along the pathways have been successfully located, it is straightforward to figure out that the oxidative addition is both the rate-determining step and the selectivity-determining step. Compared to the oxidative addition, the reductive elimination of Pd(IV) complexes are more feasible. Moreover, inspection of the mapped free profile suggests the C(acyl_EDG)−O bond cleavage is kinetically preferred over that of the C(acyl_EWG)−O bond by 11.7 kJ/ mol, indicating a ratio of rate constant as 1:0.009. Efforts were also taken to offer a reasonable explanation for why the Pd atom prefers to interact with the electron-rich C-X bond in this case. Calculations using Merz−Kollmann scheme were first conducted to map the ESP charge distributions for these two Pd transition states TS1a and TS1b (Figure 2). Interestingly, we found the Pd atom in TS1b is more positively charged (i.e., + 0.528) than the one involved in TS1a (+0.008). It seems from our calculation that the electron-withdrawing group, when attached to the acyl rather than the carboxylic group, can significantly further lower the electron density on the Pd atom, making it even more positively charged. Along with the ESP charge analysis, the distortion/ interaction analysis gave us some more details about the selectivity (Figure 3). The distortion is much more severe for

a The reactions were performed with 0.20 mmol of 1, carboxylic acid (0.40 mmol, 2.0 equiv), 2,4,6-trichlorobenzoyl chloride (0.40 mmol, 2.0 equiv), Pd(TFP)2Cl2 (5 mol %), and Cs2CO3 (0.80 mmol, 4.0 equiv) in 1,4-dioxane (2.0 mL). bBicyclo[2.2.1]hept-5-ene-2-carbaldehyde instead of norbornene was used. c(4-Methoxyphenyl)boronic acid (2.0 equiv) was used instead of ethyl acrylate. dIn the absence of ethyl acrylate. e2-(Cyclohex-1-en-1-yl)acetic acid (4.0 equiv) was used. The products were characterized after hydrogenation.

acid as termination reagent resulted in a low yield (4k). The reaction of 2-iodotoluene and 2-iodoanisole derivatives performed equally efficiently for this ortho acylation reaction (4l−o). With carboxylic acids bearing a proper C−C double bond, ring-fused compounds 3,4-dihydronaphthalen-1(2H)one analogues could be synthesized efficiently in one step from aryl iodides (4p−t). The utility of this transformation was further demonstrated by the 1.0 mmol scale reactions of 4i and 4p, which gave comparative or better yields. The reaction of 4-fluoro-1-iodo-2-methylbenzene 1f gave a mixture of 4u and 3f with a ratio of 1.5:1, indicating that the selectivity was also influenced by the substituents on aryl halides though the origin of this observation is tentatively unclear to date (Scheme 6a). The use of highly bulky carboxylic acids (e.g., 2,2-dimethylbutanoic acid or 1-adamantanecarboxylic acid) resulted in the formation of 2,4,6-trichlorobenzoyl compound 3g exclusively (Scheme 6b). These results indicated

Figure 3. Distortion/interaction analysis (activation strain model) for both types of oxidative additions

the anhydride involved in TS1b than the one in TS1a. Meanwhile, the distortion energies for the Pd complexes are almost same in these two different types of addition (TS1a of +16.2 kJ/mol vs TS1b of +13.2 kJ/mol). It implies that breaking the O−C1 bond is more difficult than cleaving the O− C2 bond. In light of the above rationale, our effort then focused on the ortho acylation by the use of aliphatic carboxylic acids, particularly for those α-nonbranched carboxylic acids, which were usually poor substrates in previous studies. After the optimization of reaction conditions, it was found that the reaction in 1,4-dioxane with Cs2CO3 as the base proceeded most efficiently (Scheme 5). The reaction of 1-iodonaphthalene with primary or secondary aliphatic acids, such as acetic acid and pentanoic acid, proceeded smoothly to deliver the corresponding ketone in good yields (4a−c, 4j), where the phenyl group, ester, ether, and amide functional groups were also compatible (4d−h). The use of p-methoxyphenyl boronic

Scheme 6. Substrate Scope

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DOI: 10.1021/acs.orglett.7b03514 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

(7) Catellani, M.; Frignani, F.; Rangoni, A. Angew. Chem., Int. Ed. Engl. 1997, 36, 119. (8) (a) Catellani, M. Synlett 2003, 298. (b) Lautens, M.; Alberico, D.; Bressy, C.; Fang, Y.-Q.; Mariampillai, B.; Wilhelm, T. Pure Appl. Chem. 2006, 78, 251. (c) Catellani, M.; Motti, E.; Della Ca’, N.; Ferraccioli, R. Eur. J. Org. Chem. 2007, 2007, 4153. (d) Catellani, M.; Motti, E.; Della Ca’, N. Acc. Chem. Res. 2008, 41, 1512. (e) Martins, A.; Mariampillai, B.; Lautens. Top. Curr. Chem. 2009, 292, 1. (f) Ferraccioli, R. Synthesis 2013, 45, 581. (g) Ye, J.-T.; Lautens, M. Nat. Chem. 2015, 7, 863. (9) For some typical reports, see: (a) Lautens, M.; Piguel, S. Angew. Chem., Int. Ed. 2000, 39, 1045. (b) Faccini, F.; Motti, E.; Catellani, M. J. Am. Chem. Soc. 2004, 126, 78. (c) Martins, A.; Candito, D. A.; Lautens, M. Org. Lett. 2010, 12, 5186. (d) Chai, D. I.; Thansandote, P.; Lautens, M. Chem. - Eur. J. 2011, 17, 8175. (e) Larraufie, M.-H.; Maestri, G.; Beaume, A.; Derat, E.; Ollivier, C.; Fensterbank, L.; Courillon, C.; Lacote, E.; Catellani, M.; Malacria, M. Angew. Chem., Int. Ed. 2011, 50, 12253. (f) Jiao, L.; Bach, T. J. Am. Chem. Soc. 2011, 133, 12990. (g) Liu, H.; El-Salfiti, M.; Lautens, M. Angew. Chem., Int. Ed. 2012, 51, 9846. (h) Zhang, H.; Chen, P.; Liu, G. Angew. Chem., Int. Ed. 2014, 53, 10174. (i) Pan, S.-F.; Ma, X.-J.; Zhong, D.-N.; Chen, W.-Z.; Liu, M.-C.; Wu, H.-Y. Adv. Synth. Catal. 2015, 357, 3052. (j) Lei, C.; Jin, X.; Zhou, J. Angew. Chem., Int. Ed. 2015, 54, 13397. (k) Shi, H.; Babinski, D. J.; Ritter, T. J. Am. Chem. Soc. 2015, 137, 3775. (l) Luo, B.; Gao, J.-M.; Lautens, M. Org. Lett. 2016, 18, 4166. (m) Zhang, B.-S.; Hua, H.-L.; Gao, L.-Y.; Qiu, Y.-F.; Zhou, P.-X.; Zhou, Z.-Z.; Zhao, J.H.; Liang, Y.-M. Org. Chem. Front. 2017, 4, 1376. (n) Zuo, Z.; Wang, H.; Fan, L.; Liu, J.; Wang, Y.; Luan, X. Angew. Chem., Int. Ed. 2017, 56, 2767. (o) Fan, L.; Liu, J.; Bai, L.; Wang, Y.; Luan, X. Angew. Chem., Int. Ed. 2017, 56, 14257. (10) Examples of oxidative addition of other related Pd(II) palladacycles: (a) Sickert, M.; Weinstabl, H.; Peters, B.; Hou, X.; Lautens, M. Angew. Chem., Int. Ed. 2014, 53, 5147. (b) Chen, D.; Shi, G.; Jiang, H.; Zhang, Y.; Zhang, Y. Org. Lett. 2016, 18, 2130. (c) Pan, S.; Jiang, H.; Zhang, Y.; Chen, D.; Zhang, Y. Org. Lett. 2016, 18, 5192. (d) Wu, Z.; Ma, D.; Zhou, B.; Ji, X.; Ma, X.; Wang, X.; Zhang, Y. Angew. Chem., Int. Ed. 2017, 56, 12288. (e) Ye, J.; Shi, Z.; Sperger, T.; Yasukawa, Y.; Kingston, C.; Schoenebeck; Lautens, M. Nat. Chem. 2017, 9, 361. (11) (a) Weinstabl, H.; Suhartono, M.; Qureshi, Z.; Lautens. Angew. Chem., Int. Ed. 2013, 52, 5305. (b) Sui, X.; Zhu, R.; Li, G.; Ma, X.; Gu, Z. J. Am. Chem. Soc. 2013, 135, 9318. (12) (a) Jiao, L.; Herdtweck, E.; Bach, T. J. Am. Chem. Soc. 2012, 134, 14563. (b) Jiao, L.; Bach, T. Angew. Chem., Int. Ed. 2013, 52, 6080. (13) (a) Wang, X.-C.; Gong, W.; Fang, L.-Z.; Zhu, R.-Y.; Li, S.; Engle, K. M.; Yu, J.-Q. Nature 2015, 519, 334. (b) Dong, Z.; Wang, J.; Dong, G. J. Am. Chem. Soc. 2015, 137, 5887. (c) Shen, P.-X.; Wang, X.-C.; Wang, P.; Zhu, R.-Y.; Yu, J.-Q. J. Am. Chem. Soc. 2015, 137, 11574. (d) Shi, H.; Wang, P.; Suzuki, S.; Farmer, M. E.; Yu, J.-Q. J. Am. Chem. Soc. 2016, 138, 14876. (14) (a) Zhou, P.-X.; Ye, Y.-Y.; Liu, C.; Zhao, L.-B.; Hou, J.-Y.; Chen, D.-Q.; Tang, Q.; Wang, A.-Q.; Zhang, J.-Y.; Huang, Q.-X.; Xu, P.-F.; Liang, Y.-M. ACS Catal. 2015, 5, 4927. (b) Dong, Z.; Wang, J.; Ren, Z.; Dong, G. Angew. Chem., Int. Ed. 2015, 54, 12664. (c) Huang, Y.; Zhu, R.; Zhao, K.; Gu, Z. Angew. Chem., Int. Ed. 2015, 54, 12669. (d) Sun, F.; Li, M.; He, C.; Wang, B.; Li, B.; Sui, X.; Gu, Z. J. Am. Chem. Soc. 2016, 138, 7456. (15) Wang, J.; Zhang, L.; Dong, Z.; Dong, G. Chem. 2016, 1, 581. (16) (a) Becke, A. D. Phys. Rev. A: At., Mol., Opt. Phys. 1988, 38, 3098. (b) Becke, A. D. J. Chem. Phys. 1993, 98, 1372−1377. (c) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B: Condens. Matter Mater. Phys. 1988, 37, 785. (17) Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H. J. Chem. Phys. 2010, 132, 154104. (18) Cardenas, D. J.; Martin-Matute, B.; Echavarren, A. M. J. Am. Chem. Soc. 2006, 128, 5033.

that the electron-deficient aryl acyl groups still could be transferred by the use of bulky reagents. In summary, we have developed a practical palladium/ norbornene-catalyzed protocol for introducing aliphatic acyl group to the ortho position of aryl iodides. An electronic effect played a vital role in chemical selectivity, rather than the steric effect. DFT calculation indicated that the electron-donating group on the phenyl acyl moiety can stabilize the positive charged Pd(IV) intermediate by increasing the electron density on the Pd(IV) atom.

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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.7b03514. Experimental procedure, spectroscopic data, and 1H and 13 C NMR spectra of the products (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Julong Jiang: 0000-0002-2357-1127 Yao Fu: 0000-0003-2282-4839 Zhenhua Gu: 0000-0001-8168-2012 Author Contributions †

S.X. and J.J. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was partly supported by NSFC (21472179, 21622206, 21325208, 21572212), the ’973’ project from the MOST of China (2015CB856600). The supercomputer center in the USTC is also acknowledged for providing the computational resources.

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REFERENCES

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DOI: 10.1021/acs.orglett.7b03514 Org. Lett. XXXX, XXX, XXX−XXX