Palladium-Catalyzed Direct Dehydrogenative Annulation of

Apr 22, 2014 - 3(4H)-ones via Pd-catalyzed direct dehydrogenative annulations of ferrocene- carboxamides with internal alkynes in air has been develop...
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Palladium-Catalyzed Direct Dehydrogenative Annulation of Ferrocenecarboxamides with Alkynes in Air Wucheng Xie,† Bin Li,† Shansheng Xu,† Haibin Song,† and Baiquan Wang*,†,‡ †

State Key Laboratory of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), College of Chemistry, Nankai University, Tianjin 300071, People’s Republic of China ‡ State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, People’s Republic of China S Supporting Information *

ABSTRACT: A novel method to synthesize racemic ferrocene[1,2-c]pyridine3(4H)-ones via Pd-catalyzed direct dehydrogenative annulations of ferrocenecarboxamides with internal alkynes in air has been developed. Both alkyl and aryl ferrocenecarboxamides can be applied as effective substrates.

O

rhodium-,6,7 and ruthenium-catalyzed8,9 oxidative couplings of various aromatic substrates with alkynes have been extensively investigated, leading to diverse cyclic compounds (Scheme 1, eq 1).

rganometallic complexes have been proven to be excellent candidates as antitumoral agents. Among them, ferrocene and its derivatives have aroused great interest because of their promising bioactivities.1 Frequently, when a ferrocene fragment is attached to or replaces a benzene ring of biologically active molecules, their biological activities are enhanced significantly (Figure 1).2 Recently, incorporating a ferrocene moiety into purely organic drugs has become a pioneering strategy in the enhancement of therapeutic effectiveness.3

Scheme 1. Transition-Metal-Catalyzed Oxidative Heterocycle Synthesis

To our knowledge, although a few examples of catalytic ferrocene C−H bond functionalization have been reported,10 no catalytic oxidative annulation reaction with alkynes to construct ferrocenyl heterocycles has yet been reported. Herein, we report the first palladium-catalyzed oxidative annulations of ferrocenecarboxamides with alkynes via N−H and C−H bond activation (Scheme 1, eq 2). To optimize the reaction condition, N-phenyl ferrocenecarboxamide (1a) was chosen as the model substrate. As shown in Table 1, by treatment of 1a (0.2 mmol) with diphenylacetylene (2a) (0.4 mmol) in the presence of catalytic amounts of Pd(OAc)2 (0.02 mmol) and Cu(OAc)2·H2O (0.1 mmol), tetrabutylammonium bromide (0.2 mmol) additives, and NaHCO3 (0.8 mmol) in toluene (1.0 mL) at 90 °C, open to

Figure 1. Representative bioactive ferrocenyl analogues.

Heterocyclic cores are essential structures and widely exist in a large proportion of drugs. Thus, it is highly desirable to develop efficient catalytic methods to synthesize ferrocenylfused analogues of heterocycles from simple and widely available starting materials. During the past decade, transition-metal-catalyzed C−H functionalization has emerged as a powerful tool to build diverse complex molecules, including various heterocyclic compounds in more efficient ways in comparison with conventional synthetic methods.4 In particular, the palladium-,5 © 2014 American Chemical Society

Received: March 11, 2014 Published: April 22, 2014 2138

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Organometallics

Communication

Table 1. Optimization of Reaction Conditionsa

Table 2. Substrate Scope of Ferrocenecarboxamidesa

entry

1a:2a

solvent

base

temp (°C)

yield (%)b

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

1:2 1:1.1 1:2 1:2 1:2 1:2 1:2 1:2 1:2 1:2 1:2 1:2 1:2 1:2

toluene toluene t-AmOH dioxane DMF toluene toluene toluene toluene toluene toluene toluene toluene toluene

NaHCO3 NaHCO3 NaHCO3 NaHCO3 NaHCO3 none K2CO3 HCO2Na·2H2O NaHCO3 NaHCO3 NaHCO3 NaHCO3 NaHCO3 NaHCO3

90 90 90 90 90 90 90 90 90 90 70 110 90 90

73 68 48 68 trace 44 67 72 trace trace 61 45 36 58

a Conditions: 1a (0.2 mmol), 2a (0.4 mmol), Pd(OAc)2 (0.02 mmol), TBAB (0.2 mmol), Cu(OAc)2·H2O (0.1 mmol), NaHCO3 (4 equiv), toluene (1.0 mL), 90 °C, 12 h, in air. Isolated yields are shown. b100 °C, 24 h.

a

Conditions: 1a (0.2 mmol), 2a (0.22−0.4 mmol), Pd(OAc)2 (0.02 mmol), TBAB (0.2 mmol), Cu(OAc)2·H2O (0.1 mmol), base (4 equiv), solvent (1.0 mL), heating in an open tube. bIsolated yield. cNo Cu(OAc)2·H2O. dNo TBAB. e2 equiv of Cu(OAc)2·H2O under Ar. f 24 h.

(3ia, 3ka) has no detrimental effect on this reaction, giving a mixture of products due to axial chirality. However, mesityl ferrocenecarboxamide (3qa) gave no product. Alkyl ferrocenecarboxamides (3oa, 3pa) successfully undergo oxidative coupling with alkynes, although showing low yields (24%, 20%). After the reaction time was increased to 24 h and the reaction was carried out at 100 °C, the product could be isolated in moderate yield (42, 40%). The molecular structure of 3pa was confirmed by single-crystal X-ray diffraction analysis (Figure 2). Other aromatic amines were also tested under these conditions; α-naphthyl amide afforded 55% yield.

air for 12 h, the desired annulation product 4,5,6triphenylferrocene[1,2-c]pyridine-3(4H)-one (3aa) was obtained in 73% yield (entry 1, Table 1). The structure of 3aa was confirmed by its 1H and 13C NMR spectra and mass spectrometry data. The yield of 3aa decreased slightly to 68% with 1.1 equiv of 2a. Other solvents such as dioxane, t-AmOH, and DMF were less effective (entries 3−5, Table 1). When no base or other bases such as K2CO3 and HCOONa·2H2O were used instead of NaHCO3, the yield decreased (entries 6−8). Cu(OAc)2·H2O and TBAB were essential to the reaction. When the reaction was carried out in the absence of Cu(OAc)2· H2O or TBAB, no annulation product was detected (entries 9 and 10). Notably, when the reaction was carried out under an Ar atmosphere using 2.0 equiv of Cu(OAc)2·H2O as oxidant, the product was obtained in 36% yield (entry 13). The reaction temperature exerts a tremendous influence. When the temperature was increased to 110 °C or reduced to 70 °C, the yield decreased (entries 11 and 12). When the reaction time was extended to 24 h, the product was isolated with 58% yield, probably because the product could be consumed by oxygen (entry 13). Therefore, the optimal reaction conditions were determined: Pd(OAc)2 (10 mol %), NaHCO3 (4.0 equiv), Cu(OAc)2·H2O (0.5 equiv), TBAB (1.0 equiv), toluene, 90 °C, 12 h, in air. With the optimal reaction conditions in hand, various substituted ferrocenecarboxamides (1a−r) were treated with diphenylacetylene (2a) and produced the corresponding ferrocene[1,2-c]pyridone derivatives (Table 2). In the present catalytic reaction, halogen-substituted 4-fluoro-, 4-chloro-, and 4-bromoanilines 1b−d could also be tolerated, affording the annulation products 3ba−3da in good yields (52−65%). Amides bearing electron-donating or electron-withdrawing groups at the N-phenyl ring, aniline substituted with −CF3 (3na), -OMe (3ga), and −COOEt (3ha), reacted to give good yields. Moreover, the effect of steric hindrance was investigated. Introduction of an ortho substituent into the N-phenyl ring

Figure 2. Molecular structures of 3pa and 3ah-1.

In addition to 2a, other symmetrical alkynes (2b−g) were also tested for the present reaction (Table 3). Methyl- (2e), methoxy- (2f), fluoro- (2d), chloro- (2b), and bromosubstituted (2c) diphenylacetylenes reacted with 1a and afforded the corresponding ferrocene[1,2-c]pyridines 3ab− 3ag in moderate to good yields (38−78%). To give evidence for the regioselectivity of this reaction, a few unsymmetrical alkynes were employed. 1-Phenyl-1-propyne (2h) and ethyl 3phenylpropiolate (2i) gave the mixed products 3ah (60%, 3:1) and 3ai (50%, >8:1) in moderate to good yields. Attempts to react terminal alkynes or dialkyl alkynes were not successful, with no expected product being isolated. The electrochemical behavior of the products 3 was studied through cyclic voltammetry (CV). The CV curves exhibit the regular wave corresponding to the reversible ferrocene/ 2139

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Table 3. Substrate Scope of Alkynesa

ferrocenecarboxamides can be applied as effective substrates. A wide range of ferrocene[1,2-c]pyridines were successfully constructed with moderate to good yields. This method may contribute to the design and synthesis of new bioactive molecules containing ferrocenyl moieties. Further investigations into a detailed reaction mechanism and the application of this method in the synthesis of other ferrocene heterocycles are in progress.

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ASSOCIATED CONTENT

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AUTHOR INFORMATION

S Supporting Information *

Text, figures, a table, and CIF files giving detailed experimental procedures, characterization data for all new compounds, and X-ray structures of 3pa and 3ah-1. This material is available free of charge via the Internet at http://pubs.acs.org. Corresponding Author

*E-mail for B. Wang: [email protected].

a

Conditions: 1a (0.2 mmol), 2a (0.4 mmol), Pd(OAc)2 (0.02 mmol), TBAB (0.2 mmol), Cu(OAc)2·H2O (0.1 mmol), NaHCO3 (4 equiv), toluene (1.0 mL), 90 °C, 12 h, in air. Isolated yields are shown. b Determined by X-ray diffraction analysis and NOESY. cDetermined by NOESY.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China (Nos. 21372122, 21174068, and 21121002) and the Research Fund for the Doctoral Program of Higher Education of China (No. 20110031110009) for financial support.

ferrocenium (Fc/Fc+) redox couple (see the Supporting Information). In comparison with the value for the simple unsubstituted ferrocene, E1/2 values for 3 are shifted toward negative potentials, slightly modified by different substituents. As previously reported,5j activation of the C−H bond proceeded first, and the ferrocene[1,2-c]pyridine-3(4H)-one products were generated after the carbometalation and reductive elimination processes. In our case, after Pd(OAc)2 was subjected to the reaction system, activation of the N−H bond and the adjacent C−H bond to the amide via directing group participation with the loss of two molecules of HOAc gives the five-membered palladacycle A, which can readily undergo the regioselective insertion of an alkyne into the Pd−C bond of intermediate A to give the seven-membered palladacycle B. After the reductive elimination the desired product was obtained, the Pd(0) can be oxidized by Cu(II) to regenerate a Pd(II) species for the next catalytic cycle, and the Cu(I) could be oxidized to Cu(II) in air (Figure 3). In summary, we have developed a novel method to synthesize racemic ferrocene[1,2-c]pyridine-3(4H)-ones via Pd-catalyzed direct dehydrogenative annulations of ferrocenecarboxamides with internal alkynes. Both alkyl and aryl

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Figure 3. Proposed catalytic cycle. 2140

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