Synthesis of Ferrocenyl and Ruthenocenyl Thioamide Derivatives

Sep 13, 2013 - organometallic thioamide derivatives were unambiguously characterized by 1H ... procedure for the synthesis of ferrocenyl thioamides us...
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Synthesis of Ferrocenyl and Ruthenocenyl Thioamide Derivatives Using a Single-Step Three-Component Reaction Malay Patra,* Jeannine Hess, Sandro Konatschnig, Bernhard Spingler, and Gilles Gasser* Institute of Inorganic Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland S Supporting Information *

ABSTRACT: The efficient syntheses of various metallocenyl thioamides using a single-step three-component condensation reaction between the commercially available (dimethylaminomethyl)ferrocene or aminomethylferrocene and another organic amine in the presence of elemental sulfur are described. All new organometallic thioamide derivatives were unambiguously characterized by 1H and 13C NMR spectroscopy and mass spectrometry. Furthermore, the structures of five ferrocenyl thioamides determined by X-ray crystallography are presented.

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INTRODUCTION Thioamide is an important and useful functional group in chemistry as well as in biology. Thioamides are not only present in medicinally important molecules but are also used as building blocks for the construction of pharmacologically important molecules containing nitrogen and sulfur heterocycles,1−4 which ultimately find uses as potent antitumor agents and enzyme inhibitors.1,5−7 Very recently, the thioamide functionality was utilized as a fluorescent quencher in probes designed to monitor protein folding, function, and protein− protein interactions.8−10 Additionally, thioamide-functionalized fluorescent dyes were successfully employed as sensors for metal ions.11−13 The principles of such sensors rely on the selective desulfurization of thioamides by thiophilic metal ions. For example, Chang et al. reported a thioamide−pyrene conjugate for the selective detection of Zr4+ ion in solution.12 In the presence of Zr4+ and H2O2, the thioamide−pyrene conjugate is desulfurized and generates the corresponding amide−pyrene conjugate. This leads to a switch in fluorescence and hence to a selective detection of the Zr4+ ion. Since its serendipitous discovery in the 1950s,14 ferrocene has gained the attention of organic as well as inorganic chemists due to its very unique structure, stability, and attractive electrochemical properties.15 These characteristics have been employed for catalysis purposes,16 in material science,17−19 for biosensing applications,20,21 and more recently in the field of bioorganometallic chemistry.22−30 Ferrocene derivatives containing a thioamide functionality directly attached to the cyclopentadienyl ring were shown to be very good auxiliary substituents for the generation of cyclopalladated ferrocene derivatives31,32 as well as being useful as precursors for the synthesis of various ligands used in asymmetric organic synthesis33,34 and for the electrochemical detection of anions.35 Despite this importance, to our surprise, there have been only a few reports in the literature describing the synthesis of ferrocenyl thioamides and, more generally, of organometalliccontaining thioamide derivatives. The reason is most likely related to synthetic difficulties, since, in comparison to purely © XXXX American Chemical Society

organic compounds, organometallic complexes are sometimes more sensitive toward certain reagents and reaction conditions. To date, the typical and general routes to prepare ferrocenyl thioamides are the thionation of ferrocenyl amides35,36 (route A, Scheme 1) or ferrocenyl metal aminocarbene complexes37 (route B) using Lawesson’s reagent and S8/NaBH4, respectively. As described by Kato and co-workers, ferrocenyl thioamides can also be prepared by the reaction of suitable amines with bis(ferrocenecarbothioyl) sulfide38,39 (route C). More recently, Bertrand et al. showed that the reaction of ferrocenyl aldiminium salts with NaHMDS/S8 can yield ferrocenyl thiomide derivatives (route D).40 However, all these routes involve several synthetic steps for the preparation of the starting materials. As one-step alternatives, there are either the treatment of lithiated ferrocene with appropriate Nalkylthiocarbamoyl chloride (route E)33,41 or the reaction of ferrocene with KSCN (Friedel−Crafts type reaction)42 in the presence of strong acids (route F). Although the preparation of N,N-dimethylferrocenecarbothioamide (3o, Table 2) was reported using a Willgeror−Kindler type reaction between ferrocenecarboxaldehyde and dimethylamine (route G), the isolated yield was not given.31 Furthermore, only one example of such a reaction was provided.31 Thus, the development of an expedient and simple synthetic route to functionalized ferrocenyl thionamide remains a highly desirable target. In this work, we report, for the first time, a one-step versatile procedure for the synthesis of ferrocenyl thioamides using a three-component condensation reaction between the commercially available (dimethylaminomethyl)ferrocene (1a) or aminomethylferrocene (1b) and another organic amine in the presence of elemental sulfur (Scheme 1, route H). This synthetic procedure was further extended for the preparation of ruthenocenyl thioamide derivatives. Special Issue: Ferrocene - Beauty and Function Received: July 22, 2013

A

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Scheme 1. Diverse Synthetic Routes for the Preparation of Ferrocenyl Thioamide Derivativesa

a

Fc = (C5H5)Fe(C5H4), Fc′ = (C5Me5)Fe(C5Me4), MSA = methanesulfonic acid.

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RESULTS AND DISCUSSION Optimization of Reaction Conditions. In previous reports by McMillan and Nguyen et al., respectively, the preparation of thioamides was described via a sulfur-mediated oxidative coupling reaction between two aliphatic amines (Scheme 2).43,44 We anticipated that an analogous reaction

yield after chromatographic purification (entry 2, Table 1). Compound 3a was characterized by 1H and 13C NMR spectroscopy and mass spectrometry as well as by elemental analysis. Importantly, a peak at 200 ppm in the 13C NMR spectrum of 3a suggested the presence of the thioamide functionality. In the ESI-MS spectrum, a peak corresponding to the [M]+ ion of 3a was detected at m/z 349. Furthermore, single crystals of 3a suitable for X-ray crystallography were grown at 4 °C from an ethyl acetate/hexane (1/2 v/v) solution of 3a. The ORTEP plot of 3a is shown in Figure 1. The Cp rings of the ferrocenyl unit are almost coplanar (dihedral angle 1.16(18)°). The C11−S1 bond is nearly in the plane of the adjacent Cp ring (3.18(15)°), indicative of a strong conjugation. The gauche conformation of the C12−C13 bond (N1−C12−C13−C14 torsion angle −58.3(3)°) leads to a compact overall molecular arrangement with rather close contacts between two hydrogen atoms of the unsubstituted Cp ring and the π system of the phenyl ring (H6a−C16 = 2.09 Å). Importantly, the successful isolation of 3a was a definitive proof that the ferrocenyl moiety could survive the harsh conditions employed in this reaction. In order to improve the yield of 3a, the influence of temperature and solvents on the reaction was investigated (see Table 1). It is worth noting that, although the reaction time could be shortened to 20 min using a microwave reactor, no significant improvement in the yield was observed (entry 3, Table 1). Furthermore, high internal pressure was observed during the reaction and, for safety reasons, we decided against pursuing our investigations with a microwave reactor. The yield was, however, significantly improved when the reaction was carried out at lower temperature (entries 4 and 5, Table 1). At 140 °C, the reaction needs ca. 70 h for complete consumption of 1a, and 3a was isolated in 68% yield (entry 5, Table 1). Interestingly, a substantial amount of 1a could still be observed if the temperature was further lowered to 110 °C, even after 12 days (entry 6, Table 1). Use of aminomethylferrocene (1b)45 instead of 1a at 140 °C provided 3a only in 24% yield (entry 7, Table 1) together with unidentified impurities. This low yield is probably due to the instability of 1b under the applied reaction conditions. However, the time required for complete

Scheme 2. Oxidative Coupling of Two Amines into Thioamides

may be utilized to synthesize metallocenyl thioamides. Therefore, as a first attempt, experimental conditions nearly identical with those used by McMillan et al. for the reaction between benzylamine and sulfur to form N-benzylthiobenzamide were employed.43 Commercially available (dimethylaminomethyl)ferrocene (1a, 1 equiv), phenylethylamine (2a, 1.3 equiv) and elemental sulfur (3.0 equiv) were heated to 200 °C in a sealed high-pressure Schlenk flask under solvent-free conditions (Table 1, entry 1).43 After 1.5 h, we found that most of 1a was evaporated and stuck to the cold portion of the inner surface of the flask and therefore remained unreacted, as monitored by TLC (silica gel, EtOAc/MeOH/ NEt3 10/2/0.5) and 1H NMR spectroscopy. Formation of only a trace amount of the desired amide 3a was observed. However, when the same reaction was performed in the presence of a solvent (decalin), 1a was consumed completely after 1.5 h and the desired ferrocenyl thioamide 3a could be isolated in a 37% B

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Table 1. Optimization of Reaction Conditionsa

entry

ferrocenylamine

solvent

temp (°C)

time

yield of 3a (%)c

1 2 3 4 5 6 7 8e

1a 1a 1a 1a 1a 1a 1b 1b

solvent freeb decalinb p-xylene or THF decalin p-xylene toluene or p-xylene p-xylene toluene

200 200 200 (microwave reactor)d 170 140 110 140 100

1.5 h 1.5 h 0.3 h 12 h 70 h 12 days 28 h 48 h

trace 37 38−43 45 68 21 24 48

a All reactions were carried out using 1 equiv of 1a (0.82 mmol) or 1b (0.41 mmol), 1.3 equiv of 2a, and 3 equiv of elemental S. bThe reaction was performed in a sealed high-pressure reaction flask. cIsolated yield after chromatographic purification. dDue to the generation of gaseous byproducts, high internal pressure is possible. It is therefore not recommended to use a microwave. eTogether with 3a, 3a′ was isolated in ca. 10% yield.

smoothly to provide the corresponding thioamide derivatives 3b−d in good yields (31−56%, entries 1−3, Table 2). For (4nitro-2-phenylethyl)amine (2c), the formation of an impurity, 3c′ (yield 13%), together with the desired compound 3c (yield 50%) was observed. In addition to the NMR spectroscopic and mass spectrometric data, the structure of 3c′ was confirmed by X-ray crystallography (Figure S2, Supporting Information). The corresponding torsion angle N1−C12−C13−C14 = −178.47(16)° for 3c′ with an anti conformation of the Cp ring led to an overall elongated molecular shape. The formation of 3c′ can be explained by taking into consideration the generation of H2S during the course of the reaction that can reduce aromatic nitro groups to amines.44,46,47 The reaction of aliphatic amino alcohols (2f,g) also proceeded smoothly (Table 2, entries 4 and 5). Thioamides 3f,g were isolated in 35% and 28% yields, respectively. In both cases, the formation of a trace amount of 3o (yield ca. 5%) as an impurity was observed (see Table 2, entry 14, for the structure). In contrast, the reaction of 1a with primary amines (2h,i) having a methyl/tert-butyl ester functionality resulted in complex mixtures (Table 2, entries 6 and 7), from which the isolation of the desired thioamides was found to be impossible. However, although it resulted in low yield (11%), the reaction of 1b with 2h was found to give the expected thioamide 3h (Table 2, entry 8). The 4-aminocarboxylic acid (2j) could be coupled with 1a, but the corresponding thioamide 3j was obtained only in a 14% yield after chromatographic purification (Table 2, entry 9). The reaction of 1a with the secondary amine 2k was also found to work and provided 3k in 39% yield. All in all, the reaction was found to be compatible with a number of functional groups such as −OH, −OMe, −NO2, −COOMe, and −COOH. However, the yields for the thioamides vary depending on the functional group present in the organic amine derivative. In order to increase the scope of this reaction, we tested the opportunity to prepare ruthenocenyl thioamides. Our group has recently assessed the possibility to prepare small

Figure 1. ORTEP plot of 3a. Hydrogen atoms, except H1A, are omitted for clarity. Ellipsoids are drawn at the 50% probability level.

consumption of 1b is significantly shorter (28 h only) in comparison to 1a (entry 7, Table 1). Again, the yield of 3a could be increased up to 48% by extending the reaction time to 48 h and lowering the reaction temperature to 100 °C (entry 8, Table 1). However, at lower temperatures, together with 3a, formation of an orange impurity was noticed. The impurity was isolated and characterized as the homocoupled product of 1b (3a′; see Table 1 for structure). The isolation of 3a′ (yield ca. 10%) is in good agreement with that described by Nguyen and co-workers, who observed the formation of the homocoupled product during the coupling reaction between benzylamine and phenylethylamine (2a).44 Condensation of Ferrocenyl-/Ruthenocenylamines with Various Organic Amines. With the optimized reaction conditions in hand, we investigated the scope of this reaction for the preparation of various ferrocenyl thioamides (see Tables 2 and 3). As shown in Table 2, the reactions between 1a and various aliphatic amines were examined. The reaction of 1a and different 4-substituted 2-phenylethylamines (2b−d) proceeded C

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Table 2. Condensation of (Dimethylaminomethyl)ferrocene/-ruthenocene and Aminomethylferrocene with Aliphatic Aminesd

The reaction was done in a sealed high-pressure reaction flask. bIsolated yield after chromatographic purification. cA mixture of 3 mL of p-xylene and 0.5 mL of pyridine used as solvent. dAll reactions were performed on a scale of 1 equiv of 1a (0.82 mmol) or 1b (0.41 mmol), 1.3 equiv of organic amine, and 3 equiv of elemental sulfur. All reactions involving 1a,c−e as starting materials were carried out at 140 °C, but the reaction involving 1b (entry 8) as starting material was carried out at 100 °C. a

ruthenocenyl derivatives, encouraged by the recent report that ruthenocene-containing complexes could have interesting antimalarial properties.48,49 As anticipated, the ruthenocenyl thioamide 3l could be obtained in 62% yield when (dimethylaminomethyl)ruthenocene (1c)50 was treated with 2a (Table 2, entry 12). Of note, 3l is, to the best of our knowledge, the first example of a ruthenocenyl thioamide. However, our efforts to couple either 1,1 ′-bis[(dimethylamino)methyl]ferrocene (1d) 51 or 1,1′-bis[(dimethylamino)methyl]ruthenocene (1e)50 with 1a were unsuccessful. Both reactions resulted in complex mixtures which could not be separated. Interestingly, it was found that the thioamide 3o could be isolated in 28% yield when 1a was heated only with sulfur in the absence of a partner organic amine (Table 2, entry 14). In order to check the feasibility of a similar coupling reaction between 1a and aromatic amines, a mixture of 1a (1 equiv), aniline (4a, 1.5 equiv), and elemental sulfur (3.5 equiv) in pxylene was refluxed at 140 °C for 65 h. The desired thioamide 5a was isolated in 34% yield after chromatographic purification (Table 3, entry 1). Some minor and unidentified impurities also formed. One of them was characterized as 3o. Unfortunately, changing the reaction conditions or increasing the number of equivalents of either one or both reactants (aniline and sulfur)

did not significantly improve the yield of the desired product. Nevertheless, to the best of our knowledge, this is the first example of such thionation coupling between an aliphatic metallocenyl amine and an aromatic amine. As shown in Table 3, various functionalized aromatic amines could be successfully coupled with 1a under the reaction conditions described in this article to yield the respective thioamides in good yields. It is worth mentioning that, due to the reduced nucleophilicity of the aromatic amines, the formation of a trace amount of 3o was observed during every reaction. Unfortunately, the reaction between 1a and either 4e or 4f yielded complex mixtures. Of note, attempts were made to verify the potential of this thionation coupling reaction for the labeling of biomolecules, such as peptides (4g,h) bearing α-Ala-NH2 as the terminal amino acid on the solid phase (Table 3, entry 7). Unfortunately, the desired products could neither be traced by LC-MS nor be isolated.

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CONCLUSION In conclusion, an expedient one-step three-component synthetic route to ferrocenyl thioamides starting from (dimethylaminomethyl)ferrocene (1a) or aminomethylferrocene (1b) is described in this article. We demonstrated that the thionation coupling of 1b with the organic amine works at D

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Table 3. Condensation of 1a with Aromatic Amines

a

Isolated yield after chromatographic purification. All reactions were performed on a scale of 1 equiv of 1a (0.82 mmol), 1.5 equiv of organic amine, and 3.5 equiv of elemental sulfur. bAll reactions were performed on a scale of 1 equiv of 1b, 2 equiv of resin-bound peptides 4g (resin-Gly-Phe-(αAla)-NH2) and 4h (resin-Gly-Phe-(α-Ala)-(β-Ala)-NH2), and 3.0 equiv of elemental sulfur. The reaction mixtures involving 4g,h were refluxed in toluene at 100 °C for 24 h.

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lower temperature in comparison to 1a. The methodology was further extended to the synthesis of ruthenocenyl thioamides. To the best of our knowledge, this is one of the most straightforward synthetic route to diverse metallocenyl thioamides reported so far. We expect that the method presented herein will allow more of these compounds to be used in various fields of research in the near future.

EXPERIMENTAL SECTION

Materials. All chemicals were of reagent grade quality or better, obtained from commercial suppliers and used without further purification. Solvents were used as received or dried over molecular sieves. All preparations were carried out using standard Schlenk techniques. Aminomethylferrocene (1b),45 (dimethylaminomethyl)ruthenocene (1c),50 1,1′-bis[(dimethylamino)methyl]ferrocene (1d),51 and 1,1′-bis[(dimethylamino)methyl]ruthenocene (1e)50 were prepared following standard literature procedures. Peptides E

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4.26 (s, 5H, C5H5), 4.29 (m, 2H, C5H4), 4.44 (m, 2H, C5H4), 4.59 (d, J = 4.7 Hz, 2H, CH2), 4.85 (m, 2H, C5H4), 7.39 (s, br, 1H, NH). 13C NMR (125 MHz, CDCl3): δ (ppm) 45.5, 68.6, 68.7, 68.8, 68.9, 70.9, 71.4, 83.7, 83.9, 198.7. Anal. Calcd for C22H21Fe2NS: C, 59.62; H, 4.78; N, 3.16. Found: C, 59.27; H, 4.91; N, 3.02. ESI-MS (positive detection mode): m/z (%) 365.9 (100) [M + Na]+. Compound 3b. The compound was purified by flash column chromatography (silica gel, hexane/EtOAc 6/1 → 4/1). 3b was isolated as a red-orange solid (yield 170.3 mg, 56%). Rf = 0.31 (silica gel, hexane/EtOAc 4/1). Mp: 138.5 °C. 1H NMR (500 MHz, CDCl3): δ (ppm) 2.92 (t, 2H, J = 6.4 Hz, CH2), 3.75 (s, 3H, OCH3), 3.96−4.01 (m, 7H, CH2 and C5H5), 4.31 (m, 2H, C5H4), 4.65 (m, 2H, C5H4), 6.85 (d, J = 8.4 Hz, 2H, C6H5), 7.12−7.16 (m, 3H, NH and C6H5). 13 C NMR (100 MHz, CDCl3): δ (ppm) 33.7, 46.9, 55.8, 69.1, 71.1, 71.4, 84.4, 114.9, 130.3, 130.8, 159.2, 200.1. ESI-MS (positive detection mode): m/z (%) 402.1 (100) [M + Na]+. Compounds 3c and 3c′. The compound was purified by flash column chromatography (silica gel, hexane/EtOAc 3/1 → 2/1 → 1/ 1). Two orange bands from the column were collected. The first orange band gave 3c as an orange solid (yield 161 mg, 50%). Rf = 0.51 (silica gel, hexane/EtOAc 1.5/1). Mp: 171.5 °C. 1H NMR (400 MHz, CDCl3): δ (ppm) 3.13 (t, br, 2H, CH2), 3.97−4.06 (m, 7H, CH2 and C5H5), 4.36 (m, 2H, C5H4), 4.72 (m, 2H, C5H4), 7.31 (s, br, 1H, NH), 7.41 (d, J = 7.8 Hz, 2H, C6H4), 8.12 (d, J = 7.8 Hz, 2H, C6H4). 13C NMR (100 MHz, CDCl3): δ (ppm) 34.7, 46.2, 69.171.2, 71.7, 84.1, 124.4, 132.2, 146.9, 147.4, 200.7. ESI-MS (positive detection mode): m/z (%) 417.0 (100) [M + Na]+. HRMS (ESI): calcd for C19H18FeN2NaO2S 417.0336, found 417.0332. The second orange band gave 3c′ as an orange solid (yield 39 mg, 13%). Rf = 0.20 (silica gel, hexane/EtOAc 1.5/1). Mp: 154.1 °C. 1H NMR (500 MHz, CDCl3): δ (ppm) 2.96 (t, J = 6.6 Hz, 2H, CH2), 4.02 (q, 2H, CH2), 4.09 (s, 5H, C5H5), 4.41 (m, 2H, C5H4), 4.73 (m, 2H, C5H4), 6.74 (d, J = 8.3 Hz, 2H, C6H4), 7.12 (d, J = 8.3 Hz, 2H, C6H4), 7.23 (s, br, 1H, NH). 13C NMR (125 MHz, CDCl3): δ (ppm) 33.1, 46.3, 68.5, 70.5, 70.9, 83.9, 115.6, 128.1, 129.5, 145.2, 199.5. ESIMS (positive detection mode): m/z (%) 387.1 (100) [M + Na]+. Compound 3d. The compound was purified by flash column chromatography (silica gel, hexane/EtOAc 5/1 → 3/1). 3d was isolated as a red-orange solid (yield 102 mg, 31%). Rf = 0.26 (silica gel, hexane/EtOAc 3/1). Mp: 158.9 °C. 1H NMR (500 MHz, CDCl3): δ (ppm) 3.15 (t, J = 6.7 Hz, 2H, CH2), 3.95 (s, 3H, OCH3), 4.08−4.15 (m, 7H, C5H5 and CH2), 4.43 (m, 2H, C5H4), 4.76 (m, 2H, C5H4), 7.24 (s, br, 1H, NH), 7.42 (d, J = 8.0 Hz, 2H, C6H4), 8.07 (d, 2H, J = 8.0 Hz, C6H4). 13C NMR (100 MHz, CDCl3): δ (ppm) 34.2, 45.8, 52.1, 68.5, 70.6, 71.1, 83.8, 128.8, 128.9, 130.1, 143.9, 166.8, 200.1. ESI-MS (positive detection mode): m/z (%) 430.0 (100) [M + Na]+. HRMS (ESI): calcd for C21H21NNaFeO2S 430.0540, found 430.0537. Compound 3f. The compound was purified by flash column chromatography (silica gel, hexane/EtOAc 3/1 → 1/1). 3f was isolated as an orange oil that solidified after standing at room temperature for several days (yield 98 mg, 35%). Rf = 0.17 (silica gel, hexane/EtOAc 1/1). Mp: 85.7 °C. 1H NMR (400 MHz, CDCl3): δ (ppm) 1.40 (m, 5H, OH and 2 × CH2), 1.55 (m, 2H, CH2), 1.69 (m, 2H, CH2), 3.60, (m, 2H, CH2), 3.72 (m, 2H, CH2), 4.11 (s, 5H, C5H5), 4.36 (m, 2H, C5H4), 4.78 (m, 2H, C5H4), 7.24 (s, 1H, br, NH). 13 C NMR (100 MHz, CDCl3): δ (ppm) 25.9, 27.2, 28.9, 33.1, 46.1, 63.3, 69.1, 71.5, 71.6, 84.4, 200.2. ESI-MS (positive detection mode): m/z (%) 368.1 (100) [M + Na]+. HRMS (ESI): calcd for C17H23FeNNaOS 368.0747, found 368.0746. Compound 3g. The compound was purified by flash column chromatography (silica gel, hexane/EtOAc 3/1 → 1/2). 3g was isolated as an orange oil that solidified after standing at room temperature for several days (yield 73 mg, 28%). Rf = 0.13 (silica gel, hexane/EtOAc 1/1). 1H NMR (400 MHz, CDCl3): δ (ppm) 1.77 (m, 2H, CH2), 1.91 (m, 2H, CH2), 2.02 (s, 1H, br, OH), 3.81 (m, 4H, 2 × CH2), 4.21 (s, 5H, C5H5), 4.44 (m, 2H, C5H4), 4.90 (m, 2H, C5H4), 7.94 (s, 1H, br, NH). 13C NMR (100 MHz, CDCl3): δ (ppm) 24.9, 29.4, 45.7, 62.1, 68.7, 70.8, 71.1, 83.8, 199.2. ESI-MS (positive detection mode): m/z (%) 340 (100) [M + Na]+. HRMS (ESI): calcd for C15H19FeNNaOS 340.0435, found 340.0428.

4g,h were synthesized using standard Fmoc solid-phase synthesis procedures52 on Tenta Gel S RAM resin and characterized by LC-MS or mass spectrometry. Instrumentation and Methods. 1H and 13C NMR spectra were recorded in deuterated solvents on 400 (1H, 400 MHz; 13C, 100 MHz) and 500 MHz (1H, 500 MHz; 13C, 125 MHz) spectrometers at room temperature. The chemical shifts, δ, are reported in ppm (parts per million). The residual solvent peaks have been used as an internal reference. The abbreviations for the peak multiplicities are as follows: s (singlet), d (doublet), dd (doublet of doublets), t (triplet), q (quartet), m (multiplet), and br (broad). ESI mass spectra were recorded on a Bruker Esquire 6000 spectrometer. Elemental microanalyses were performed on a LecoCHNS-932 elemental analyzer. Melting points were determined on a Mettler Toledo MP70 Melting Point System. The LC-MS spectra were measured on an Acquity from Waters system equipped with a PDA detector and an auto sampler using an Agilent Zorbax 300SB-C18 analytical column (3.5 μm particle size, 300 Å pore size, 150 × 4.6 mm). This LC was coupled to an Esquire HCT apparatus from Bruker (Bremen, Germany) for the MS measurements. The LC run (flow rate 0.3 mL min−1) was performed with a linear gradient of A (distilled water containing 0.1% v/v formic acid) and B (acetonitrile Sigma-Aldrich HPLC grade): t = 0 min, 0% B; t = 1 min, 0% B; t = 20 min, 66% B. X-ray Crystallography. Crystallographic data were collected at 183(2) K with either Mo Kα radiation (λ = 0.7107 Å) or Cu Kα radiation (λ = 1.54184 Å). Compounds 3c′ and 5b were measured on an Agilent SuperNova Dual source, with an Atlas detector, while compounds 3a,b,k were measured on an Oxford Diffraction CCD Xcalibur system with a Ruby detector. Suitable crystals were covered with oil (Infineum V8512, formerly known as Paratone N), placed on a nylon loop that was mounted in a CrystalCap Magnetic from Hampton Research, and immediately transferred to the diffractometer. The program suite CrysAlisPro was used for data collection, multiscan absorption correction, and data reduction.53 The structures were solved with direct methods using SIR9754 and were refined by fullmatrix least-squares methods on F2 with SHELXL-97.55 The structures were checked for higher symmetry with help of the program Platon.56 All CIF files are available in the Supporting Information. General Procedure (GP-1). A mixture of metallocenylamine (1 equiv), organic amine (1.3 equiv for aliphatic amines and 1.5 equiv for aromatic amines), and elemental sulfur (3 equiv for aliphatic amines and 3.5 equiv for aromatic organic amines) was taken either in a sealed high-pressure reaction flask or in a 25 mL round-bottom flask fitted with a reflux condenser. A 3 mL portion of the solvent was added, and the mixture was heated and stirred under an argon atmosphere for the required time period. A similar procedure was used for the reactions under solvent-free conditions. Unless otherwise stated, all the reaction were preferably carried out in a 25 mL round-bottom flask fitted with a reflux condenser. After being cooled to room temperature, the crude reaction mixture was purified by silica gel column chromatography. The band for the desired compound can be easily traced due to the orange color of the ferrocenyl thioamide derivatives. In some cases, the purification step may need to be repeated to remove completely the unreacted sulfur. The reaction times and yields are presented in Tables 1−3. Characterization Data. Compound 3a. The compound was purified by flash column chromatography (silica gel, hexane/EtOAc 6/ 1 → 5/1). 3a was isolated as a red-orange solid. Rf = 0.30 (silica gel, hexane/EtOAc 4/1). Mp: 163.8 °C. 1H NMR (500 MHz, CDCl3): δ (ppm) 3.09 (t, J = 6.6 Hz, 2H, CH2), 4.06 (s, 5H, C5H5), 4.09 (m, 2H, CH2), 4.40 (m, 2H, C5H4), 4.72 (m, 2H, C5H4), 7.21 (s, br, 1H, NH), 7.32−7.34 (m, 3H, C6H5), 7.40−7.43 (m, 2H, C6H5). 13C NMR (125 MHz, CDCl3): δ (ppm) 34.1, 46.1, 68.5, 70.5, 71.1, 83.8, 127.1, 128.5, 129.1, 138.4, 199.7. Anal. Calcd for C19H19FeNS: C, 65.34; H, 5.48; N, 4.01. Found: C, 65.50; H, 5.44; N, 4.08. ESI-MS (positive detection mode): m/z (%) 349.1 (100) [M]+. Compound 3a′. The compound was purified by flash column chromatography (silica gel, hexane/EtOAc 6/1). 3a′ was isolated as a brownish red solid. Rf = 0.40 (silica gel, hexane/EtOAc 6/1). 1H NMR (500 MHz, CDCl3): δ (ppm) 4.19 (s, 5H, C5H5), 4.23 (m, 2H, C5H4), F

dx.doi.org/10.1021/om400715m | Organometallics XXXX, XXX, XXX−XXX

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Article

Compound 3h. The compound was purified by flash column chromatography (silica gel, hexane/EtOAc 4/1 → 2/1). 3h was isolated as an orange oil (yield 16 mg, 11%). Rf = 0.28 (silica gel, hexane/EtOAc 3/1). 1H NMR (400 MHz, CDCl3): δ (ppm) 2.07− 2.13 (dt, J = 12.2, 6.2 Hz, 2H, CH2), 2.57 (t, J = 6.3 Hz, 2H, CH2), 3.78 (s, 3H, OCH3), 3.82−3.88 (m, 2H, CH2), 4.20 (s, 5H, C5H5), 4.45 (m, 2H, C5H4), 4.93 (m, 2H, C5H4), 8.11 (s, br, 1H, NH). 13C NMR (100 MHz, CDCl3): δ (ppm) 22.7, 32.2, 45.9, 52.1, 68.7, 70.6, 71.1, 83.6, 174.9, 199.6. ESI-MS (positive detection mode): m/z (%) 368.1 (100) [M + Na]+. HRMS (ESI): calcd for C16H19FeNNaO2S 368.0384, found 368.0379. Compound 3j. The compound was purified by flash column chromatography (silica gel, EtOAc/MeOH 1/0 → 12/1). 3j was isolated as an orange oil that solidified after standing at room temperature for several days (yield 37 mg, 14%). Rf = 0.37 (silica gel, EtOAc). 1H NMR (500 MHz, CDCl3): δ (ppm) 2.13 (m, 2H, CH2), 2.61 (m, 2H, CH2), 3.88 (m, 2H, CH2), 4.19 (s, 5H, C5H5), 4.46 (m, 2H, C5H4), 4.89 (m, 2H, C5H4), 7.84 (s, br, 1H, NH). 13C NMR (125 MHz, CDCl3): δ (ppm) 22.9, 31.7, 45.5, 68.8, 70.8, 71.1, 83.4, 177.9, 200.1. ESI-MS (positive detection mode): m/z (%) 354.1 (100) [M + Na]+. HRMS (ESI): calcd for C15H17FeNNaO2S 354.0227, found 354.0222. Compound 3k. The compound was purified by flash column chromatography (silica gel, hexane/EtOAc 5/1 → 4/1). 3k was isolated as an orange solid (yield 101 mg, 39%). Rf = 0.29 (silica gel, hexane/EtOAc 4/1). Mp: 162.1 °C. 1H NMR (500 MHz, CDCl3): δ (ppm) 3.73 (m, 4H, 2 × CH2), 4.05−4.23 (m, 9H, C5H5, 2 × CH2), 4.37 (m, 2H, C5H4), 4.62 (m, 2H, C5H4). 13C NMR (100 MHz, CDCl3): δ (ppm) 53.1, 67.3, 69.1, 72.1, 72.5, 88.2, 200.1. ESI-MS (positive detection mode): m/z (%) 316.1 (100) [M + H]+. Compound 3l. The compound was purified by flash column chromatography (silica gel, hexane/EtOAc 6/1 → 4/1). 3l was isolated as a white crystalline solid (yield 84 mg, 62%). Rf = 0.39 (silica gel, hexane/EtOAc 4/1). Mp: 159.6 °C. 1H NMR (400 MHz, CDCl3): δ (ppm) 3.04 (t, J = 6.6 Hz, 2H, CH2), 4.01 (m, 2H, CH2), 4.41 (s, 5H, C5H5), 4.66 (m, 2H, C5H4), 5.05 (m, 2H, C5H4), 7.31−7.43 (m, 6H, NH and C6H5). 13C NMR (100 MHz, CDCl3): δ (ppm) 33.7, 46.1, 70.6, 72.1, 72.3, 90.2, 127.1, 128.6, 128.9, 138.4, 198.9. ESI-MS (positive detection mode): m/z (%) 418.3 (100) [M + Na]+. HRMS (ESI): calcd for C19H19NNaRuS 418.0179, found 418.0182. Compound 3o.31 The compound was purified by flash column chromatography (silica gel, hexane/EtOAc 5/1 → 3/1). 3o was isolated as an orange-red solid (yield 62 mg, 28%). Rf = 0.61 (silica gel, hexane/EtOAc 4/1). 1H NMR (400 MHz, CDCl3): δ (ppm) 3.45 (s, br, 3H, NCH3) and 3.53 (s, br, 3H, NCH3), 4.26 (s, 5H, C5H4), 4.39 (m, 2H, C5H4), 4.74 (m, 2H, C5H4). 13C NMR (100 MHz, CDCl3): δ (ppm) 44.1, 44.9, 69.2, 71.1, 72.1, 87.3, 199.8. ESI-MS (positive detection mode): m/z (%) 296.0 (100) [M + Na]+. HRMS (ESI): calcd for C13H15NNaFeS 296.0172, found 296.0166. Compound 5a. The compound was purified by flash column chromatography (silica gel, hexane/EtOAc 5/1 → 4/1). 5a was isolated as an orange-red solid (yield 86 mg, 32%). Rf = 0.38 (silica gel, hexane/EtOAc 4/1). Mp: 131.6 °C. 1H NMR (500 MHz, CDCl3): δ (ppm) 4.29 (s, 5H, C5H5), 4.54 (m, 2H, C5H4), 4.98 (m, 2H, C5H4), 7.29−7.31 (m, 1H, C6H5), 7.45−7.49 (m, 2H, C6H5), 7.74−7.77 (m, 2H, C6H5), 8.81 (s, br, 1H, NH). 13C NMR (125 MHz, CDCl3): δ (ppm) 68.9, 70.8, 71.6, 85.1, 123.8, 126.6, 129.1, 138.8, 199.4. ESI-MS (positive detection mode): m/z (%) 344.1 (100) [M + Na]+. HRMS (ESI): calcd for C17H15NNaFeS 344.0172, found 344.0168. Compound 5b. The compound was purified by flash column chromatography (silica gel, hexane/EtOAc 4/1 → 3/1). 5b was isolated as an orange-red solid (yield 103 mg, 36%). Rf = 0.37 (silica gel, hexane/EtOAc 3/1). Mp: 165.1 °C. 1H NMR (500 MHz, CDCl3): δ (ppm) 3.86 (s, 3H, OCH3), 4.28 (s, 5H, C5H5), 4.53 (m, 2H, C5H4), 4.98 (m, 2H, C5H4), 6.99 (d, 2H, J = 8.1 Hz, C6H4), 7.59 (d, 2H, J = 8.1 Hz, C6H4), 8.70 (s, br, 1H, NH). 13C NMR (125 MHz, CDCl3): δ (ppm) 55.5, 68.9, 70.5, 71.5, 84.6, 114.1, 126.1, 131.7, 158.1, 199.2. ESI-MS (positive detection mode): m/z (%) 374.1 (100) [M + Na]+. Compound 5c. The compound was purified by flash column chromatography (silica gel, hexane/EtOAc 3.5/1 → 2.5/1). 5c was

isolated as an orange-red solid (yield 60 mg, 19%). Rf = 0.37 (silica gel, hexane/EtOAc 2.5/1). Mp: 132.1 °C. 1H NMR (500 MHz, CDCl3): δ (ppm) 3.95 (s, 3H, OCH3), 4.29 (s, 5H, C5H5), 4.57 (m, 2H, C5H4), 4.99 (m, 2H, C5H4), 7.92 (d, J = 8.1 Hz, 2H), 8.12 (d, J = 8.1 Hz, 2H), 8.87 (s, br, 1H). 13C NMR (125 MHz, CDCl3): δ (ppm) 51.1, 69.1, 71.1, 71.9, 84.2, 122.2, 127.4, 130.5, 142.8, 166.3, 200.2. ESI-MS (positive detection mode): m/z (%) 380.0 (100) [M + H]+. HRMS (ESI): calcd for C19H17NNaFeO2S 402.0227, found 402.0224. Compound 5d. The compound was purified by flash column chromatography (silica gel, hexane/EtOAc 5/1). 5d was isolated as an orange-red solid (yield 71 mg, 24%). Rf = 0.23 (silica gel, hexane/ EtOAc 5/1). Mp: 126.0 °C. 1H NMR (400 MHz, CDCl3): δ (ppm) 4.28 (s, 5H, C5H5), 4.59 (m, 2H, C5H4), 4.99 (m, 2H, C5H4), 7.48 (d, J = 8.0 Hz, 2H, C6H4), 7.65 (d, J = 8.0 Hz, 2H, C6H4), 8.71 (s, br, 1H, NH). 13C NMR (100 MHz, CDCl3): δ (ppm) 70.1, 71.2, 84.2, 125.9, 129.4, 132.5, 138.8, 200.1. ESI-MS (positive detection mode): m/z (%) 378.0 (100) [M + H]+. HRMS (ESI): calcd for C17H14NNaFeClS 377.9783, found 377.9779.

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ASSOCIATED CONTENT

S Supporting Information *

Cif files and figures giving ORTEP plots of 3b,c′,k and 5b, 1H and 13C NMR spectra and LC-MS traces of 4g,h. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Authors

*M.P.: e-mail, [email protected]. *G.G.: e-mail, [email protected]; fax, +41 44 635 6803; tel, +41 44 635 4630; web, www.gassergroup.com. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was financially supported by the Swiss National Science Foundation (SNSF Professorship PP00P2_133568), the University of Zurich, and the Stiftung für wissenschafltiche Forschung of the University of Zurich.

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REFERENCES

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dx.doi.org/10.1021/om400715m | Organometallics XXXX, XXX, XXX−XXX