Palladium-Catalyzed Formylation of Aryl Iodides with HCOOH as CO

Letter pubs.acs.org/OrgLett

Palladium-Catalyzed Formylation of Aryl Iodides with HCOOH as CO Source Guanglong Sun,‡,§,∥ Xue Lv,‡,§,∥ Yinan Zhang,† Min Lei,*,‡,§ and Lihong Hu*,† †

Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Stake Key Laboratory Cultivation Base for TCM Quality and Efficacy, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, P. R. China ‡ Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P. R. China § University of Chinese Academy of Sciences, Beijing 100049, P. R. China S Supporting Information *

ABSTRACT: A facile and practical method for the synthesis of aromatic aldehydes by palladium-catalyzed reductive carbonylation starting from aryl iodides and HCOOH is described. Compared to the known formylation procedure, HCOOH serves not only as the most convenient and environmental-friendly C1 source but also as the reviving agent in the reductive elimination process of a Pd-catalyst. Furthermore, this procedure is also applied successfully to the modification of natural products, such as vindoline, tabersonin, and vincamine, to obtain the corresponding products in good yields.

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palladium-catalyzed formylation (Figure 1b), such as Nformylsaccharin, 8 9-methylfluorene-9-carbonyl chloride, 9 CO2,10 paraformaldehyde,11 acetic formic anhydride,12 Fe(CO)5,13 and S-phenyl thioformate,14 extra reductants (e.g., silanes or metals reagents) are essential in most of the cases due to the palladium redox cycle in the coupling reaction. The only exceptional example also required acetic anhydride to generate acetic formic anhydride in situ, which may cause an unnecessary acetylation on the substrates with active function groups.15 Therefore, formylation procedures that are efficient and benign to diverse function groups and the environment are still highly requested. In recent years, formic acid as a carbonylation source is reported.16 Since formic acid itself could play as a reducing agent to the oxidative palladium, the finding of a trigger to release carbon monoxide from formic acid would benefit the formylation. Herein, we utilized I2 and triphenylphosphine to promote the formic acid formylation (Figure 1c), which circumvented the aforementioned drawbacks and provided versatile functionalized aromatic aldehydes with high yields. Initially, to exam whether I2 could promote HCOOH as a CO provider, we carried out the formylation of 4-methoxyiodobenzene 1a with extra PPh3 and I2 in acetonitrile. After refluxing for 2 h at 80 °C, the desired product 3a was formed in 57% yield. This result clearly indicated that HCOOH played both formylating and reducing roles with the help of I2 (see Scheme S1 in the Supporting Information (SI)). To further improve the yield, a series of optimizationss were performed and summarized in Table 1. Initially, to study the solvent effect, several solvents were screened, and the results suggested that the solvent had a

romatic aldehyde is one of the critical synthetic blocks in the consequent formation of various C−C and C−X bonds. Its synthetic applications are widely distributed in the areas of pharmaceuticals, food additives, pesticides, chemical materials, and so on,1 thus receiving historic attention from chemists.2 Electrophilic formylation is the conventional method to access aromatic aldehydes, including Duff reaction and Casiraghi reaction,1,3 Vilsmeier reaction,4 and Gattermann− Koch reaction (Reimer−Tiemann reaction) (Figure 1a).5

Figure 1. Palladium-catalyzed reductive carbonylation of aryl halides.

Although the direct introduction of the fomyl group ensures the highest synthetic efficiency, the requirement of electron-rich aromatic systems as well as the incompatibility of plenty function groups limits the scope of substrates. Along with the discovery of palladium-catalyzed carbonylzation,6 carbon monoxide became a powerful C1 source to form aromatic aldehydes especially in industrial side.7 However, laboratorial utilization of gaseous CO suffered from storage, transportation, handling, and safety regulations. Even though a series of C1 surrogates have been significantly explored in © XXXX American Chemical Society

Received: June 20, 2017

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DOI: 10.1021/acs.orglett.7b01882 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Table 1. Solvent and Catalyst Screeninga

Scheme 1. Reaction of Aryl Iodides with HCOOHa,b

entry

solvent

[Pd] (equiv)

I2

PPh3 (equiv)

yieldb (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

MeCN THF DMF DCM Py toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene

Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(TFA)2 PdSO4 PdCl2 Pd2(dba)3 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2

1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.2 1.1 1.2 1.2 1.2 1.2

1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.4 1.3 1.2 1.1

57 53 48 71 67 77 75 66 73 60 78 59 80 82 76 75

a Reaction conditions: 1a (1 mmol), 2 (8 mmol), I2, PPh3, [Pd] (5 mol %), Et3N (10 mmol), solvent (4 mL), 80 °C, 2 h. bYields were determined by LC-MS.

significant impact on the yields of 3a and toluene displayed the best yield at 77% (Table 1, entries 1−6 and Table S1 in SI). Further examination of palladium sources proved Pd(OAc)2 was the best option in terms of efficiency, and the loading amount was found to be as low as 3 mol % (Table 1, entries 6− 10 and Tables S3 and S4 in the SI). The optimal ratio of PPh3 and I2 was further investigated (Table 1, entries 11−16 and Tables S7 and S8 in the SI), and the results revealed slightly higher equivalences than the substrate were needed. After extensive experimentation (see Tables S1−S10 in the SI), the optimal conditions were established as HCOOH (4 equiv), Pd(OAc)2 (3.0 mol %), I2 (1.2 equiv), PPh3 (1.2 equiv), and Et3N (6 equiv) in toluene at 80 °C for 2−4 h. Moreover, an 83% yield was obtained on a 10 mmol scale, which proved the potential practicality of this conversion. However, no improvement took place with different leaving groups, such as Br−, Cl−, TsO−, and TfO− (see Table S11 in the SI). To explore the generality and scope of the formylation, various aryl iodides were reacted under the optimal conditions (Scheme 1). As shown in Scheme 1, the positions of substitutions have little effect on the yield and all the ortho, meta, and para aryl iodides underwent the formylation smoothly with good yields in the range 68−92% (3a−l). Traditional forbidden substrates (3m−p and 3t−w) with electron-withdrawing substituents were tolerated in this conversion, though the yields of para-nitro and para-cyano dropped to a moderate level. It is also worth noting that the desired formylating products were smoothly obtained from the substrates with active functional groups (3r−u), which were ineligible in the acetic anhydride promoted formylation.15 Furthermore, electron-donating and -withdraing hetereoaromatic aldehydes could also be achieved by HCOOH formylation (3v−y). To further support its application, aryl di-iodides were used as starting material to the formylation reaction. It was found

a

Standard conditions: 1 (1 mmol), 2 (4 mmol), I2 (2.4 equiv), PPh3 (2.4 equiv), Pd(OAc)2 (3 mol %), Et3N (6 mmol), toluene (4 mL), 80 °C, 2 h. bIsolated yields. cThe reaction proceeded for 4 h.

that the ortho-phthalaldehyde was sluggish to obtain, probably due to the interference of palladium oxidative addition by the neighboring carbonyl group (Scheme 2). Recently, modification of indole alkaloids received wide attention.17 Therefore, the formylation reaction was also examined on several alkaloid natural products (Scheme 3). The results showed that vindoline, tabersonin, and apovincamine were successfully transferred to their formylated analogs (7−9a) through a two-step conversion with 75%, 85%, and 68% yields, respectively. During the process, no other byproducts were clearly observed. In order to determine the hydrogen source of the aldehyde group, we carried out the reaction with isotopically labeled B

DOI: 10.1021/acs.orglett.7b01882 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 2. Reaction of Aryl Di-iodides with HCOOHa,b

Scheme 4. Reaction of 1a with DCOODa,b

a

Standard conditions: 1 (1 mmol), DCOOD (4 mmol), I2 (1.2 equiv), PPh3 (1.2 equiv), Pd(OAc)2 (3 mol %), Et3N (6 mmol), toluene (4 mL), 80 °C, 4 h. bIsolated yields.

Scheme 5. Plausible Mechanism for Reductive Carbonylation

a

Standard conditions: 4-6 (1 mmol), 2 (8 mmol), I2 (2.4 equiv), PPh3 (2.4 equiv), Pd(OAc)2 (6 mol %), Et3N (12 mmol), toluene (8 mL), 80 °C, 4 h. bIsolated yields.

Scheme 3. Reaction of Natural Products with HCOOHa,b

arylpalladium formic acid complex D and released HI simultaneously. Final decarboxylation furnished the reductive elimination to regenerate Pd(II) that launched another catalytic cycle. The elimination of carbon dioxide was confirmed by the formation of CaCO3 after exporting the gas phase of the reaction to a clear Ca(OH)2 solution. In conclusion, we have developed a facile and practical procedure for the synthesis of aromatic aldehydes by palladiumcatalyzed reductive fomylation starting from aryl iodides and dual-role HCOOH. The products are obtained in moderate to excellent yields avoiding the use of CO gas and additional reductant. It is noteworthy that this protocol is also suitable for the direct modification of natural products. The mild reaction conditions, short reaction time, and compatibility with versatile functional groups make our methodology a valid and alternative contribution to the existing processes for the synthesis of aromatic aldehydes.

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a

Stndard conditions: 7−9 (1 mmol), 2 (4 mmol), I2 (1.2 equiv), PPh3 (1.2 equiv), Pd(OAc)2 (3 mol %), Et3N (6 mmol), toluene (4 mL), 80 °C, 2 h. bIsolated yields.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b01882. Experimental procedures and spectral data for all compound (PDF)

reagent D2-formic acid. As shown in Scheme 4, the result clearly indicated the hydrogen source of the aldehyde group derived from formic acid. Based on the experimental results and previous reports, a plausible reaction mechanism was proposed (Scheme 5). Initially, I2 and PPh3 formed complex A, which helps to trigger the release of CO from formic acid. Through a ligand exchange, CO was captured by aryl palladium intermediate B generated from a rapid oxidative addition of palladium to aryl iodide. After CO insertion, the benzoylpalladium halide C converted to

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AUTHOR INFORMATION

Corresponding Authors

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

DOI: 10.1021/acs.orglett.7b01882 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters ORCID

(16) (a) Ren, W.; Chang, W.; Dai, J.; Shi, Y.; Li, J.; Shi, Y. J. Am. Chem. Soc. 2016, 138, 14864. (b) Somasunderam, A.; Alper, H. J. Mol. Catal. 1994, 92, 35. (c) El Ali, B. E.; Vasapollo, G.; Alper, H. J. Mol. Catal. A: Chem. 1996, 112, 195. (17) (a) Yang, Y.; Qiu, X.; Zhao, Y.; Mu, Y.; Shi, Z. J. Am. Chem. Soc. 2016, 138, 495. (b) Yang, Y.; Li, R.; Zhao, Y.; Zhao, D.; Shi, Z. J. Am. Chem. Soc. 2016, 138, 8734. (c) Yang, Y.; Gao, P.; Zhao, Y.; Shi, Z. Angew. Chem., Int. Ed. 2017, 56, 3966; Angew. Chem. 2017, 129, 4024.

Min Lei: 0000-0001-8696-9696 Author Contributions ∥

G.S. and X.L. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This research was supported by the National Natural Science Foundation of China (Grants 81473110, 81561148011), Special Fund for Strategic Pilot Technology Chinese Academy of Sciences (XDA12040303), the Science Foundation of Shanghai (Grant 15431901100), and the Priority Academic Program Development of Jiangsu Higher Education Institutions.

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DOI: 10.1021/acs.orglett.7b01882 Org. Lett. XXXX, XXX, XXX−XXX