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Ruthenium-catalyzed cyclocarbonylation of aliphatic amides through the regioselective activation of unactivated C(sp3)–H bonds
Tetrahedron 69 (2013) 4466e4472
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Ruthenium-catalyzed cyclocarbonylation of aliphatic amides through the regioselective activation of unactivated C(sp3)eH bonds Nao Hasegawa, Kaname Shibata, Valentine Charra, Satoshi Inoue, Yoshiya Fukumoto, Naoto Chatani * Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 29 November 2012 Received in revised form 28 January 2013 Accepted 1 February 2013 Available online 8 February 2013
The regioselective carbonylation of unactivated C(sp3)eH bonds of aliphatic amides, using 2pyridinylmethylamine as a directing group in conjunction with Ru3(CO)12 as a catalyst is described. The presence of a 2-pyridinylmethylamine moiety in the amides is crucial for the success of the reaction. Although ethylene is not incorporated into the products, its presence is also essential for the reaction to proceed. Furthermore, the addition of H2O is important for the reaction to proceed efficiently. The reaction shows a high preference for the CeH bonds of methyl groups, compared to methylene CeH bonds, even the methylene CeH bonds are activated by the presence of an oxygen atom or an aryl group. In addition, the reaction tolerates various functional groups, such as MeO, Cl, CF3, CN, and even Br substituents. The reaction of a-mono-substituted aliphatic amides gave the corresponding carbonylation products in lower yields, although the use of a,a-di-substituted aliphatic amides resulted in high product yields. The use of a sterically demanding directing group, such as 1-(2-pyridinylethyl)amine moiety, in amono-substituted aliphatic amides improved the yields of the products. The stoichiometric reaction of an amide with Ru3(CO)12 gave a stable di-nuclear ruthenium complex as a single ruthenium complex in which the 2-pyridinylmethylamino moiety is coordinated to the ruthenium center in a N,N-manner and an amide carbonyl oxygen binds to the other ruthenium center, but CeH bond activation is not involved. The complex itself does not show catalytic activity, but is activated in the presence of H2O under the catalytic reaction conditions employed. Ó 2013 Elsevier Ltd. All rights reserved.
Keywords: Ruthenium Catalysis Carbonylation CeH bond activation Chelation
1. Introduction The use of carbon monoxide (CO) in carbonyl reactions is one of the important methods for introducing carbonyl functionalities, such as acids, esters, lactones, amides, lactams, aldehydes, alcohols, and related functional groups both in the laboratory and on an industrial scale.1 A representative example involves the hydroformylation of propene (Oxo process), which, except for polymerization, is the largest industrial catalytic process. A wide variety of substrates have been used in carbonylation reactions reported. If CeH bonds, which are ubiquitous in organic molecules could be directly used in carbonylation reactions, it would provide a new possibility for exploring new types of atom economical reactions.2 In fact, surprisingly, CeH bonds were reported to participate in carbonylation a long time ago. To the best of our knowledge, the first effective example of the chelation-assisted carbonylation of CeH bonds was reported in 1955 by Murahashi,3 who carried out
* Corresponding author. Tel.: þ81 6 6879 7397; fax: þ81 6 6879 7396; e-mail address: [email protected] (N. Chatani). 0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tet.2013.02.006
the cobalt-catalyzed cyclocarbonylation of aromatic imines, which involves the carbonylation of C(sp2)eH bonds. The catalytic carbonylation of CeH bonds is an attractive method for the direct preparation of carbonyl compounds from aromatic compounds. In fact, Pd-catalyzed chelation-assistance systems have been used in the carbonylation of C(sp2)eH bonds.4,5 It was also found that Ru3(CO)12 catalyzes the regioselective carbonylation of CeH bonds in a variety of N(sp2)-containing compounds.6 However, compared with the extensively studied carbonylation of C(sp2)eH bonds,4e6 effective examples of the carbonylation of C(sp3)eH bonds were rare when we started this project.4g Tanaka reported on the Rhcatalyzed carbonylation of alkanes to produce aliphatic aldehydes under photo-irradiation conditions.7 Because of its endothermic nature, the reaction requires continuous photo-irradiation and alkanes must be used as the solvent. A wide variety of products are formed, including secondary products. We previously reported on the Rh-catalyzed carbonylation of C(sp3)eH bonds in amines.6k However, in this case, a nitrogen atom adjacent to the CeH bond was required for the carbonylation to proceed. Transition metal catalysis has recently emerged as a powerful tool for functionalizing C(sp2)eH bonds and a variety of transformations of C(sp2)eH
N. Hasegawa et al. / Tetrahedron 69 (2013) 4466e4472
bonds has already been developed. In this context, many groups have focused their attention on the functionalization of C(sp3)eH bonds, which is a more challenging topic.8 We recently reported on the development of N,N-bidentate directing group-assisted system9 in which a 2-pyridinylmethylamino group is used for the carbonylation of C(sp2)eH bonds in aromatic amides.10 In recent years, N,N-bidentate directing group systems have been used in the transformation of C(sp3)eH bonds.11 To broaden the scope of this approach, we applied the system to the carbonylation of C(sp3)eH bonds in aliphatic amides. We wish to report herein on the Rucatalyzed cyclocarbonylation of aliphatic amides through the regioselective activation of unactivated C(sp3)eH bonds.12
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11, was found to promote CeH bond carbonylation, but the yield of the corresponding carbonylation product was only 18%.
2. Results and discussion The reaction of amide 1a with CO and ethylene in the presence of Ru3(CO)12 in toluene at 160 C for 1 day gave the succinimide 2a in 22% yield, with 60% of 1a being recovered (Scheme 1). Running the reaction for 3 days resulted in an increase in product yield to 55%. Similar to the case of aromatic amides,10 ethylene, and H2O were found to have a positive effect on the outcome of the reaction. When the reaction was run in the absence of H2O, the yield of 2a decreased dramatically to 16%. The presence of ethylene is also crucial for the reaction to proceed, although it is not incorporated into the products. In fact, in the absence of ethylene, no carbonylation product was detected. The role of ethylene is not clear, but we speculate that it functions as a hydrogen acceptor. To test this hypothesis, other compounds, which are known to serve as hydrogen acceptors including norbornene, alkynes, and a,b-unsaturated carbonyl compounds were examined. When the ethylene was replaced with tert-butyl acrylate, the carbonylation product 2a was produced in 62% yield. After optimizing the reaction conditions, the following conditions were finally selected as standard reaction conditions: amide (1 mmol), CO (10 atm), ethylene (7 atm), H2O (2 mmol), Ru3(CO)12 (0.05 mmol), toluene (3 mL) as the solvent with the reaction run at 160 C for a period of 5 days.
Scheme 1. Carbonylation of unactivated C(sp3)eH bonds in amide 1a.
We next examined the effect of a directing group (Scheme 2). The reaction of N-4-pyridynylmethyl amide 3 did not result in the formation of the expected CeH bond carbonylation product, but, instead, 5 was formed in 94% yield. The reaction proceeds via two known, successive reactions: the Ru-catalyzed CeH bond carbonylation at the 2-position of pyridine leading to 46a and the Rucatalyzed [2þ2þ1] cycloaddition of the resulting pyridinyl ketones 4.13 No reaction occurred when the corresponding benzyl amide 6 was used as the substrate, in place of 1a, indicating that the coordination of the pyridine nitrogen to the catalyst is a key step for the reaction to proceed. Amides having shorter and longer carbon chains, such as 7 and 8 also did not give the corresponding imides. The oxazoline-based N,N-bidentate 914 and the N,S-bidentate system 1011e were also ineffective. An 8-aminoquinoline moiety, as in
Scheme 2. Effect of directing groups.
Table 1 shows some representative results for reactions of a,adi-substituted aliphatic amides under the standard reaction conditions. The carbonylation proceeded in highly regioselective manner. The reactions occurred exclusively at methyl CeH bonds, not at methylene CeH bonds, as shown in the reaction of 1b. Fivemembered ring formation occurred preferentially over sixmembered ring formation. Thus, the reaction of 1b gave a derivative of ethosuximide 2b, which is a succinimide anticonvulsant, that is, used mainly in the treatment of absence seizures, in 83% yield. Even when a methylene group is activated by the presence of a phenyl group, as in 1dek, or a methoxy group, as in 1l, methyl CeH bonds were selectively carbonylated. This selectivity can be attributed to steric factors. The reaction tolerated certain functional groups, such as MeO, Cl, CF3, CN, and even Br groups under the reaction conditions used. A sterically bulky aryl group, such as the pentamethylphenyl group, had no effect on the efficiency of the reaction. In the case of the cyclopropane substrate 1o, carbonylation of a methyl C(sp3)eH competed with that of the cyclopropane CeH bond, leading to a nearly 2:1 mixture of 12 and 2o.15 The carbonylation of CeH bonds in a benzene ring took place preferentially over the CeH bonds in a methyl group. Thus, the reaction of 1p gave 13 in 90% yield through C(sp2)eH bond activation, along with a small amount (<5%) of succinimide, which was formed through C(sp3)eH bond activation. As shown in the reaction of 1b, five-membered ring closing carbonylation occurred preferentially over six-membered ring closure. Even when 14 or 15 were used as the starting substrate, no corresponding six-membered carbonylation products formed. Even the presence of a nitrogen atom, cyclohexane CeH bonds as in 16 did not undergo the carbonylation.
While various a,a-di-substituted aliphatic amides underwent cyclocarbonylation in good yields under the current reaction
4468 Table 1 Carboylation of a,a-di-substituted aliphatic amidesa
N. Hasegawa et al. / Tetrahedron 69 (2013) 4466e4472 Table 1 (continued)
a
Reaction conditions: amide (1 mmol), CO (10 atm), ethylene (7 atm), H2O (2 mmol), Ru3(CO)12 (0.05 mmol), toluene (3 mL) at 160 °C for 5 days. b Isolated yields. c Toluene (4 mL). d Ru3(CO)12 (0.1 mmol) was used. conditions, as shown in Table 1, a a-mono-substituted aliphatic amide, such as isobutylic amide 1q gave the corresponding imide 2q in low yield, along with a variety of byproducts. This is probably because the cleavage of the C(O)eN bond in 1q took place under the reaction conditions. To avoid the cleavage of C(O)eN bonds, isobutylic amide, which contains a sterically bulky directing group, as in 1r was used as the substrate. As expected, an improved yield of 59% was obtained, but some unidentified byproducts were still produced. It was finally found that a methyl group, as in 1s is sufficiently bulky permit high yields of the product to be obtained. This newly developed directing group was applicable to other substrates, as in 1t, 1u, and 1v. While carbonylation did not take place at the methylene CeH bond in a cyclohexane ring, as in 1m (Table 1), the cyclobutane substrate 1v gave the corresponding carbonylation product 2v. The presence of a methyl or a phenyl group at the benzylic position improved the efficiency of the reaction of a-mono-substituted aliphatic amides, as shown in Table 2. This prompted us to examine the applicability of the new directing group in reactions of a,a-disubstituted aliphatic amides. If this directing group could be used, it would provide the opportunity to develop the enantioselective synthesis of succinimides using a chiral directing group. However, the observed diastereoselectivity was nearly 1:1, although the carbonylation products were obtained in good yields (Scheme 3). To gain insights into the mechanism of the reaction, deuterated 1m-CD3 was subjected to the reaction conditions with a low catalyst loading (5 mol %) to stop the reaction before it reached completion, in order to recover the starting amide (Scheme 4). Even at 68% conversion, no HeD exchange in the methyl group of the recovered starting amide 1m-CD3 was detected, indicating that the cleavage of the CeH bond is irreversible. In contrast, a significant amount of H/D exchange was observed at the methylene group a to the carbonyl group in product 2m. Because the methylene CeH bonds in 2m are acidic protons, H/D exchange between the CeH bonds and H2O readily took place under the reaction conditions
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and 1m-CD3. The results indicated that 1m reacts 1.8 times faster than 1m-CD3.
Table 2 Carbonylation of a-mono-substituted aliphatic amidesa
Scheme 4. Deuterium labeling experiment.
We next performed an intramolecular competitive experiment using 1d-(CH3)(CD3), in which the CeH bond reacts 3.8 times faster than CeD bond (Scheme 5).17 It was also found that that 1d is 3.6 times more reactive than 1d-(CD3)2 in an intermolecular competitive experiment. These results suggest that the cleavage of CeH bonds is the rate determining step in this new carbonylation reaction.
e
c,d
a
Reaction conditions: amide (1 mmol), CO (10 atm), ethylene (7 atm), H2O (2 mmol), Ru3(CO)12 (0.05 mmol), toluene (3 mL) at 160 °C for 5 days. b Isolated yields. A number in parenthesis is a diastereoisomeric ratio. c Ru3(CO)12 (0.15 mmol) was used. d 7 days. e Ru3(CO)12 (0.10 mmol) was used. employed. H/D Exchange at the methylene CeH bond in the 2pyridinylmethyl group also took place. The mechanism of the H/D exchange is not clear at the present time, it is well known that CeH bonds adjacent to a nitrogen atom can be activated.16 We next performed an intermolecular competition experiment using 1m Scheme 5. Competition experiments.
Scheme 3.
A stoichiometric reaction of amide 1a (0.02 mmol) with Ru3(CO)12 (0.007 mmol) was carried out in toluene at 130 C under N2, which resulted in the formation of the di-nuclear ruthenium complex 21, the structure of which was confirmed by X-ray crystallography (Fig. 1). Similar to the case of aromatic amides,10 the 2pyridinylmethylamine moiety is coordinated to the ruthenium center in an N,N-fashion and the carbonyl oxygen binds to the other ruthenium center. A proposed mechanism for the reaction, based on the results obtained, is shown in Scheme 6. A mono ruthenium species is proposed as a key catalytic species, although we were not able to collect any direct evidence for this. Coordination of a pyridine nitrogen in amide 1a to a ruthenium center followed by the oxidative
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N. Hasegawa et al. / Tetrahedron 69 (2013) 4466e4472
suggests that this process has potential for exploring new types of CeH bond transformations that cannot be achieved when conventional chelation-assisted systems are used.9e12,19 4. Experimental section 4.1. General
Fig. 1. ORTEP drawing of 21.
addition of an NeH bond gives the ruthenium hydride complex 23. The insertion of ethylene, followed by irreversible CeH bond cleavage, gives ruthenacycle 25 with the simultaneous generation of ethane. The cleavage of the CeH bond probably takes place through s-bond metathesis of the complex 24.18 The insertion of CO and subsequent reductive elimination affords the final product, with the regeneration of the mono ruthenium species. The fact that no carbonylation product was formed in the absence of ethylene suggests that no direct cleavage of a CeH bond takes place in complex 23 and that ethylene functions as a hydrogen acceptor. The complex 21 does not participate in the main catalytic cycle but, rather, exists in a resting state. The presence of H2O is also important in terms of increasing the efficiency of the reaction, as shown in Scheme 1. The role of H2O appears to be to reduce the resting complex 21 by reduction, such as the water gas shift reaction19 to give the mono ruthenium species, which completes the catalytic cycle.
1 H NMR and 13C NMR spectra were recorded on a JEOL JNMEX270, JEOL JNM-ECS400, or VARIAN UNITY-INOVA600 spectrometer in CDCl3 with tetramethylsilane as the internal standard. Data are reported as follows: chemical shifts in parts per million (d), multiplicity (s¼singlet, d¼doublet, t¼triplet, q¼quartet, sept¼septuplicate, bs¼broad singlet, and m¼multiplet), coupling constant (Hertz), integration, and interpretation. Infrared spectra (IR) were collected on a Horiba FT-720 spectrometer; absorption. Mass spectra were obtained on Shimadzu GCMS-QP 2014 and Shimadzu GCMS-QP 5000 instruments with ionization voltages of 70 eV. Melting points were determined on a Yamato melting point apparatus and are uncorrected. Elemental analyses were performed by the Elemental Analysis Section of Osaka University. High resolution mass spectra (HRMS) were obtained on a JEOL JMS-DX303 instrument. Analytical gas chromatography (GC) was carried out on Shimadzu GC-14B, Shimadzu GC-2014, and Shimadzu GC-8A gas chromatographs, equipped with flame ionization detectors. Flash column chromatography was performed with SiO2 (Silicycle Silica Gel 60 (230e400 mesh)).
4.2. Typical procedure for carbonylation of amides (1) Ru3(CO)12 (32.5 mg, 0.05 mmol), N-(pyridin-2-ylmethyl)pivalamide (1a, 1 mmol), water (36 mL, 2 mmol), and toluene (3 mL) were placed in a 50-mL stainless steel autoclave under an atmosphere of nitrogen. After flushing the system with 7 atm of ethylene three times, it was pressurized to 7 atm and then with carbon monoxide to an additional 10 atm. The autoclave was heated in an oil bath at 160 C for 5 d. The autoclave was cooled to rt, and the excess CO and ethylene were released. After transferring the contents to a round-bottom flask with CHCl3, the reaction mixture was checked by NMR and GC analysis. The volatiles were removed in vacuo, and the residue was subjected to flash column chromatography on silica-gel (eluent; Hexane/EtOAc¼6/4) to give (2a) (172 mg, 79% yield based on 1a) as a yellow oil. Distillation in vacuo gave a colorless oil. 4.3. Characterization data
Scheme 6. Proposed mechanism.
3. Conclusion In conclusion, we report on a new method for the carbonylation of unactivated C(sp3)eH bonds. The reaction of aliphatic amides with CO in the presence of Ru3(CO)12 gave cyclocarbonylation products. The presence of a 2-pyridynylmethylamino moiety, as an N,N-bidentate directing group in the substrates is crucial for the success of the reaction. The reaction proceeds selectively at a methyl CeH bond over a methylene CeH bond. The reaction tolerates a variety of functional groups. The carbonylation of C(sp3)eH bonds was achieved by the presence of N,N-bidentate directing group. This
4.3.1. 1-(1-(Pyridin-2-yl)ethyl)pyrrolidine-2,5-dione (2s). Colorless oil. Rf¼0.17 (Hexane/EtOAc¼1/1). 1H NMR (400 MHz, CDCl3): d 1.34 (dd, J¼10.0, 7.2, 3H), 1.82 (d, J¼6.8, 3H), 2.30e2.39 (m, 1H), 2.81e2.98 (m, 2H), 5.46 (q, J¼7.2, 1H), 7.16 (dd, J¼4.8, 7.2, 1H), 7.35 (d, J¼8.0, 1H), 7.66 (dt, J¼1.6, 8.0, 1H), 8.52 (d, J¼4.4, 1H). 13C NMR (100 MHz, CDCl3): d 15.73, 15.82, 16.72, 34.44, 34.50, 36.34, 50.80, 50.86, 120.60, 120.67, 122.11, 136.35, 136.37, 149.04, 158.10, 176.23, 180.37. IR (neat): 3456 w, 1774 m, 1704 s, 1591 s, 1572 w, 1471 m, 1435 m, 1396 s, 1363 s, 1292 m, 1228 m, 1120 s, 1153 w, 1122 m, 1078 w, 1041 m, 1016 w, 993 w, 947 w, 916 w, 883 w, 802 m, 773 m, 750 m, 690 w, 607 w. MS, m/z (relative intensity, %): 218 (Mþ, 18), 106 (100), 79 (34), 78 (16). HRMS: calcd for C12H14N2O2: 218.1055. Found: 218.1062. 4.3.2. 3-Benzyl-1-(1-(pyridin-2-yl)ethyl)pyrrolidine-2,5-dione (2t). Colorless oil. Rf¼0.14 (Hexane/EtOAc¼1/1). 1H NMR (399.78 MHz, CDCl3): d 1.74e1.78 (m, 3H), 2.45e2.52 (m, 1H), 2.67e2.78 (m, 1H), 2.89e3.00 (m, 1H), 3.11e3.21 (m, 1H), 5.44 (qd, J¼7.2, 7.2, 1H), 7.14e7.20 (m, 3H), 7.23e7.31 (m, 4H), 7.60e7.67 (m, 1H), 8.51e8.53
N. Hasegawa et al. / Tetrahedron 69 (2013) 4466e4472
(m, 1H). 13C NMR (100.53 MHz, CDCl3): d 15.68, 15.79, 33.05, 33.11, 36.31, 36.37, 40.93, 41.00, 50.95, 51.03, 120.65, 120.75, 122.17, 122.19, 126.96, 128.74, 129.13, 129.23, 136.41, 136.43, 137.01, 137.11, 149.12, 158.03, 176.10, 179.04. IR (neat): 1774 m, 1703 s, 1590 w, 1541 w, 1495 w, 1473 w, 1437 w, 1392 s, 1363 m, 1290 w, 1228 w, 1194 m, 1155 w, 1111 w, 1036 w, 995 w, 960 w, 920 w, 883 w, 802 w, 775 w, 750 m, 704 m, 607 w. MS, m/z (relative intensity, %): 295 (11), 294 (Mþ, 53), 293 (26), 203 (19), 121 (15), 117 (26), 115 (15), 107 (61), 106 (100), 91 (40), 79 (26), 78 (22), 65 (12), 55 (11). HRMS: calcd for C18H18N2O2: 294.1368. Found: 294.1366. 4.3.3. 3-(1-(Pyridin-2-yl)ethyl)-3-azabicyclo[3.1.0]hexane-2,4-dione (2u). White solid. Mp: 65.5 C. Rf¼0.17 (Hexane/EtOAc¼1/1). 1H NMR (400 MHz, CDCl3): d 1.47e1.52 (m, 1H), 1.64e1.67 (m, 1H), 1.77 (d, J¼7.6, 3H), 2.43e2.51 (m, 2H), 5.25 (q, J¼7.2, 1H), 7.15 (dd, J¼4.8, 7.2, 1H), 7.32 (d, J¼8.0, 1H), 7.66 (dt, J¼1.6, 8.0, 1H), 8.50 (d, J¼5.2, 1H). 13C NMR (100 MHz, CDCl3): d 16.09, 19.95, 20.09, 20.16, 49.92, 120.54, 122.14, 136.44, 149.07, 158.26, 175.03, 175.12. IR (KBr): 1772 w, 1705 s, 1591 w, 1572 w, 1473 w, 1435 w, 1387 m, 1356 m, 1188 w, 1043 w, 997 w, 949 w, 908 w, 858 w, 827 w, 804 w, 781 w, 764 w, 642 w, 609 w. MS, m/z (relative intensity, %): 216 (Mþ, 41), 147 (12), 121 (45), 120 (18), 119 (10), 107 (10), 106 (100), 105 (16), 104 (14), 95 (13), 93 (15), 79 (37), 78 (34), 70 (10), 68 (24), 55 (10), 52 (14), 51 (2). 4.3.4. 3-(1-(Pyridin-2-yl)ethyl)-3-azabicyclo[3.2.0]heptane-2,4dione (2v). Pale brown oil. Rf¼0.37 (EtOAc). 1H NMR (399.78 MHz, CDCl3): d 1.87 (d, J¼7.2 Hz, 3H), 2.16e2.32 (m, 2H), 2.58e2.72 (m, 2H), 3.26e3.32 (m, 2H), 5.52 (q, J¼7.2 Hz, 1H), 7.17 (dd, J¼8.0, 4.0 Hz, 1H), 7.39 (d, J¼8.0 Hz, 1H), 7.68 (td, J¼8.0, 1.6 Hz, 1H), 8.53 (d, J¼4.4 Hz, 1H). 13C NMR (100.53 MHz, CDCl3): d 15.71, 22.92, 23.12, 38.14, 38.21, 50.62, 120.59, 122.12, 136.45, 149.10, 158.28, 179.75, 179.83. IR (ATR): 2989 w, 2948 w, 2361 w, 2340 w, 1767 w, 1692 s, 1591 w, 1572 w, 1472 w, 1435 w, 1379 m, 1357 m, 1296 w, 1242 w, 1183 m, 1119 w, 1089 w, 1034 w, 992 w, 957 w, 927 w, 868 w, 801 w, 784 w, 762 w, 747 w. MS, m/z (relative intensity, %): 230 (Mþ, 47), 121 (25), 107 (11), 106 (100), 105 (17), 93 (13), 79 (29), 78 (23), 70 (10), 55 (14), 54 (14), 53 (16), 51 (11). HRMS: calcd for C13H14N2O2: 230.1055. Found: 230.1057. 4.3.5. 3-Benzyl-3-methyl-1-(1-(pyridin-2-yl)ethyl)pyrrolidine-2,5dione (18). Colorless oil. Rf¼0.23 (Hexane/EtOAc¼1/1). 1H NMR (399.78 MHz, CDCl3): d 1.39e1.43 (s, 3H), 1.61e1.69 (d, J¼7.4 Hz, 3H), 2.34e2.43 (d, J¼18.4 Hz, 1H), 2.68 (d, J¼13.2 Hz, 1H), 2.77e2.80 (d, J¼18.4 Hz, 1H), 3.19e3.20 (d, J¼13.2 Hz, 1H), 5.30e5.38 (q, J¼7.4 Hz, 1H), 6.98e7.19 (m, 4H), 7.24e7.26 (m, 3H), 7.55e7.61 (t, J¼7.6 Hz, 1H), 8.48, 8.50 (d, J¼4.4 Hz, 1H). 13C NMR (100.53 MHz, CDCl3): d 15.40, 15.64, 25.43, 39.35, 39.45, 43.22, 43.25, 44.58, 44.74, 50.76, 50.83, 120.32, 120.61, 121.98, 122.04, 127.05, 128.49, 128.52, 129.92, 130.04, 136.07, 136.29, 148.92, 149.01, 157.98, 158.03, 175.38, 175.45, 181.95, 182.02. IR (neat): 1774 m, 1701 s, 1591 m, 1574 w, 1495 w, 1471 m, 1454 m, 1437 m, 1394 s, 1363 s, 1288 w, 1255 w, 1228 w, 1198 s, 1153 w, 1095 w, 1074 w, 1030 w, 995 w, 957 w, 916 w, 864 w, 800 w, 768 m, 748 m, 706 m, 602 w. MS, m/z (relative intensity, %): 308 (Mþ, 28), 307 (16), 294 (17), 293 (77), 217 (12), 117 (27), 115 (12), 107 (23), 106 (100), 91 (81), 79 (20), 78 (19), 69 (10), 65 (12). HRMS: calcd for C19H20N2O2: 308.1525. Found: 308.1523. 4.3.6. 3-Benzyl-3-methyl-1-(phenyl(pyridin-2-yl)methyl)pyrrolidine-2,5-dione (20). Colorless oil. Rf¼0.31 (Hexane/EtOAc¼1/1). 1H NMR (399.78 MHz, CDCl3): d 1.41 1.43 (s, 3H), 2.38e2.42 (d, J¼18.0 Hz, 1H), 2.67e2.69 (d, J¼13.6 Hz, 1H), 2.79e2.80 (d, J¼18.0 Hz, 1H), 3.19e3.20 (d, J¼13.2 Hz, 1H), 6.45e6.47 (s, 1H), 6.89e7.06 (m, 3H), 7.13e7.31 (m, 9H), 7.51e7.56 (m, 1H), 8.50e8.54 (m, 1H). 13C NMR (100.53 MHz, CDCl3): d 25.48, 25.54, 39.33, 39.43, 42.95, 43.10, 44.74, 44.84, 59.50, 59.74, 122.04, 122.14, 122.41, 122.85, 126.89, 126.95, 127.94, 128.09, 128.39, 128.44, 128.48,
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129.10, 129.65, 129.95, 130.00, 135.99, 136.08, 136.52, 136.57, 149.02, 149.04, 156.52, 156.81, 175.27, 175.41, 181.89, 182.07. IR (neat): 1776 m, 1709 s, 1589 m, 1495 m, 1456 m, 1435 m, 1390 s, 1362 s, 1255 w, 1188 m, 1153 m, 1124 w, 1078 w, 997 w, 912 m, 791 w, 733 m, 702 s, 633 w, 611 w, 586 w. MS, m/z (relative intensity, %): 370 (Mþ, 2.9), 168 (20), 167 (100), 91 (19), 79 (29). HRMS: calcd for C24H22N2O2: 370.1681. Found: 370.1682. Acknowledgements This work was supported, in part, by a Grant-in-Aid for Scientific Research on Innovative Areas ‘Molecular Activation Directed toward Straightforward Synthesis’ from The Ministry of Education, Culture, Sports, Science and Technology. References and notes 1. For reviews on carbonylation, see: Colquhoun, H. M.; Thompson, D. J.; Twigg, M. V. Carbonylation: Direct Synthesis of Carbonyl Compounds; Plenum: New York, NY, 1991. 2. For recent reviews on functionalization of CeH bonds, see: (a) Kakiuchi, F.; Kochi, T. Synthesis 2008, 3013; (b) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624; (c) Sehnal, P.; Taylor, R. J. K.; Fairlamb, I. J. S. Chem. Rev. 2010, 110, 824; (d) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147; (e) Xu, L.-M.; Li, B.-J.; Yang, Z.; Shi, Z.-J. Chem. Soc. Rev. 2010, 39, 712; (f) Ackermann, L. Chem. Commun. 2010, 4866; (g) Ackermann, L. Chem. Rev. 2011, 111, 1315; (h) Chen, D. Y.-K.; Youn, S. W. Chem.dEur. J. 2012, 18, 9452. 3. Murahashi, S. J. Am. Chem. Soc. 1955, 77, 6403. 4. For papers on the Pd-catalyzed carbonylation of CeH bonds, see: (a) Orito, K.; Horibata, A.; Nakamura, T.; Ushito, H.; Nagasaki, H.; Yuguchi, M.; Yamashita, S.; Tokuda, M. J. Am. Chem. Soc. 2004, 126, 14342; (b) Orito, K.; Miyazawa, M.; Nakamura, T.; Horibata, A.; Ushito, H.; Nagasaki, H.; Yuguchi, M.; Yamashita, S.; Yamazaki, T.; Tokuda, M. J. Org. Chem. 2006, 71, 5951; (c) Giri, R.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 14082; (d) Houlden, C. E.; Hutchby, M.; , M. R.; Lloyd-Jones, G. C.; BookerBailey, C. D.; Ford, J. G.; Tyler, S. N. G.; Gagne Milburn, K. I. Angew. Chem., Int. Ed. 2009, 48, 1830; (e) Giri, R.; Lam, J. K.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 686; (f) Li, H.; Cai, G.-X.; Shi, Z.-J. Dalton Trans. 2010, 39, 10442; (g) Yoo, E. J.; Wasa, M.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 17378; (h) Haffemayer, B.; Gulias, M.; Gaunt, M. J. Chem. Sci. 2011, 2, 312; (i) Lu, Y.; Leow, D.; pez, B.; Rodriguez, Wang, X.; Engle, K. M.; Yu, J.-Q. Chem. Sci. 2011, 2, 967; (j) Lo A.; Santos, D.; Albert, J.; Ariza, X.; Garcia, J.; Granell, J. Chem. Commun. 2011, 1054; (k) Wrigglesworth, J. W.; Cox, B.; Lloyd-Jones, G. C.; Booker-Milburn, K. I. Org. Lett. 2011, 13, 5326; (l) Ma, B.; Wang, Y.; Peng, J.; Zhu, Q. J. Org. Chem. 2011, 76, 6362; (m) Zhang, H.; Liu, D.; Chen, C.; Liu, C.; Lei, A. Chem.dEur. J. 2011, 17, 9581; (n) Lang, R.; Shi, L.; Li, D.; Xia, C.; Li, F. Org. Lett. 2012, 14, 4130; (o) Zhang, H.; Shi, R.; Gan, P.; Liu, C.; Ding, A.; Wang, Q.; Lei, A. Angew. Chem., Int. Ed. 2012, 51, 5204; (p) Guan, Z.-H.; Chen, M.; Ren, Z.-H. J. Am. Chem. Soc. 2012, 134, 17490; (q) Liang, D.; Hu, Z.; Peng, J.; Huang, J.; Zhu, Q. Chem. Commun. 2012, 173. 5. For papers on the Rh-catalyzed carbonylation of C(sp2)eH bonds, see: Guan, Z.H.; Ren, Z.-H.; Spinella, S. M.; Yu, S.; Liang, Y.-M.; Zhang, X. J. Am. Chem. Soc. 2009, 131, 729; Du, Y.; Hyster, T. K.; Rovis, T. Chem. Commun. 2011, 12074; Lang, R.; Wu, J.; Shi, L.; Xia, C.; Li, F. Chem. Commun. 2011, 12553. 6. For papers on the Ru-catalyzed carbonylation of C(sp2)eH bonds, see: (a) Moore, E. J.; Pretzer, W. R.; O’Connell, T. J.; Harris, J.; LaBounty, L.; Chou, L.; Grimmer, S. S. J. Am. Chem. Soc. 1992, 114, 5888; (b) Chatani, N.; Fukuyama, T.; Kakiuchi, F.; Murai, S. J. Am. Chem. Soc. 1996, 118, 493; (c) Chatani, N.; Ie, Y.; Kakiuchi, F.; Murai, S. J. Org. Chem. 1997, 62, 2604; (d) Fukuyama, T.; Chatani, N.; Kakiuchi, F.; Murai, S. J. Org. Chem. 1997, 62, 5647; (e) Ishii, Y.; Chatani, N.; Kakiuchi, F.; Murai, S. Organometallics 1997, 16, 3615; (f) Ishii, Y.; Chatani, N.; Kakiuchi, F.; Murai, S. Tetrahedron Lett. 1997, 38, 7565; (g) Fukuyama, T.; Chatani, N.; Tatsumi, J.; Kakiuchi, F.; Murai, S. J. Am. Chem. Soc. 1998, 120, 11522; (h) Chatani, N.; Ishii, Y.; Ie, Y.; Kakiuchi, F.; Murai, S. J. Org. Chem. 1998, 63, 5129; (i) Ie, Y.; Chatani, N.; Ogo, T.; Marshall, D. R.; Fukuyama, T.; Kakiuchi, F.; Murai, S. J. Org. Chem. 2000, 65, 1475; (j) Chatani, N.; Fukuyama, T.; Tatamidani, H.; Kakiuchi, F.; Murai, S. J. Org. Chem. 2000, 65, 4039; (k) Chatani, N.; Asaumi, T.; Ikeda, T.; Yorimitsu, S.; Ishii, Y.; Kakiuchi, F.; Murai, S. J. Am. Chem. Soc. 2000, 122, 12882; (l) Szewczyk, J. W.; Zuckerman, R. L.; Bergman, R. G.; Ellman, J. A. Angew. Chem., Int. Ed. 2001, 40, 216; (m) Chatani, N.; Yorimitsu, S.; Asaumi, T.; Kakiuchi, F.; Murai, S. J. Org. Chem. 2002, 67, 7557; (n) Asaumi, T.; Chatani, N.; Matsuo, T.; Kakiuchi, F.; Murai, S. J. Org. Chem. 2003, 68, 7538; (o) Asaumi, T.; Matsuo, T.; Fukuyama, T.; Ie, Y.; Kakiuchi, F.; Chatani, N. J. Org. Chem. 2004, 69, 4433; (p) Chatani, N.; Uemura, T.; Asaumi, T.; Ie, Y.; Kakiuchi, F.; Murai, S. Can. J. Chem. 2005, 83, 755; (q) Imoto, S.; Uemura, T.; Kakiuchi, F.; Chatani, N. Synlett 2007, 170. 7. Sakakura, T.; Sodeyama, K.; Sasaki, K.; Wada, K.; Tanaka, M. J. Am. Chem. Soc. 1990, 112, 7221. 8. For recent reviews on functionalization of C(sp3)eH bond, see: Jazzar, R.; Hitce, J.; Renaudat, A.; Sofack-Kreutzer, J.; Baudoin, O. Chem.dEur. J. 2010, 16, 2654; Baudoin, O. Chem. Soc. Rev. 2011, 40, 4902. 9. Shiota, H.; Ano, Y.; Aihara, Y.; Fukumoto, Y.; Chatani, N. J. Am. Chem. Soc. 2011, 133, 14952. 10. Inoue, S.; Shiota, H.; Fukumoto, Y.; Chatani, N. J. Am. Chem. Soc. 2009, 131, 6898.
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11. (a) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2005, 127, 13154; (b) Reddy, B. V. S.; Reddy, L. R.; Corey, E. J. Org. Lett. 2006, 8, 3391; (c) Fneg, Y.; Chen, G. Angew. Chem., Int. Ed. 2010, 49, 958; (d) Feng, Y.; Wang, Y.; Landgraf, B.; Liu, S.; Chen, G. Org. Lett. 2010, 12, 3414; (e) Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2010, 132, 3965; (f) He, G.; Chen, G. Angew. Chem., Int. Ed. 2011, 50, 5192; (g) Ano, Y.; Tobisu, M.; Chatani, N. J. Am. Chem. Soc. 2011, 133, 12984; (h) He, G.; Zhao, Y.; Zhang, S.; Lu, C.; Chen, G. J. Am. Chem. Soc. 2012, 134, 3; (i) Nadres, E. T.; Daugulis, O. J. Am. Chem. Soc. 2012, 134, 7; (j) Xie, Y.; Yang, Y.; Huang, L.; Zhang, X.; Zhang, Y. Org. Lett. 2012, 14, 1238; (k) Rit, R. K.; Yadav, R.; Sahoo, A. K. Org. Lett. 2012, 14, 3724; (l) Zhang, S.-Y.; He, G.; Zhao, Y.; Wright, K.; Nack, W. A.; Chen, G. J. Am. Chem. Soc. 2012, n ~ ez, M. A.; 134, 7313; (m) Rodríguez, N.; Romero-Revilla, J. A.; Fern andez-Iba Carretero, J. C. Chem. Sci. 2013, 4, 175. 12. For a preliminary paper, see: Hasegawa, N.; Charra, V.; Inoue, S.; Fukumoto, Y.; Chatani, N. J. Am. Chem. Soc. 2011, 133, 8070.
13. Chatani, N.; Tobisu, M.; Asaumi, T.; Fukumoto, Y.; Murai, S. J. Am. Chem. Soc. 1999, 121, 7160; Tobisu, M.; Chatani, N.; Asaumi, T.; Akamo, K.; Ie, Y.; Fukumoto, Y.; Murai, S. J. Am. Chem. Soc. 2000, 122, 12663. See also Ref. 4g. 14. Giri, R.; Maugel, N.; Foxman, B. M.; Yu, J.-Q. Organometallics 2008, 27, 1667. 15. In the Pd-catalyzed carbonylation reaction of C(sp3)eH bonds, cyclopropane CeH bonds are selectively carbonylated. See Ref. 4g. 16. Campos, K. R. Chem. Soc. Rev. 2007, 36, 1069. 17. Similar to the case of 2m, H/D exchange at the CH2 group a to the carbonyl group and at the CH2 group in 2-pyridinylmethyl group was also observed in the carbonylation product. 18. Hartwig, J. F. Organotransition Metal Chemistry; University Science Books: Mill Valley, CA, 2010; p 285. 19. Quite recently, we reported the Ru(II)-catalyzed arylation of the ortho CeH bonds in aromatic amides through a bidentate directing system: Aihara, Y.; Chatani, N. Chem. Sci. 2013, 4, 664.
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Ruthenium-catalyzed cyclocarbonylation of aliphatic amides through the regioselective activation of unactivated C(sp3)eH bonds Nao Hasegawa, Kaname Shibata, Valentine Charra, Satoshi Inoue, Yoshiya Fukumoto, Naoto Chatani * Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 29 November 2012 Received in revised form 28 January 2013 Accepted 1 February 2013 Available online 8 February 2013
The regioselective carbonylation of unactivated C(sp3)eH bonds of aliphatic amides, using 2pyridinylmethylamine as a directing group in conjunction with Ru3(CO)12 as a catalyst is described. The presence of a 2-pyridinylmethylamine moiety in the amides is crucial for the success of the reaction. Although ethylene is not incorporated into the products, its presence is also essential for the reaction to proceed. Furthermore, the addition of H2O is important for the reaction to proceed efficiently. The reaction shows a high preference for the CeH bonds of methyl groups, compared to methylene CeH bonds, even the methylene CeH bonds are activated by the presence of an oxygen atom or an aryl group. In addition, the reaction tolerates various functional groups, such as MeO, Cl, CF3, CN, and even Br substituents. The reaction of a-mono-substituted aliphatic amides gave the corresponding carbonylation products in lower yields, although the use of a,a-di-substituted aliphatic amides resulted in high product yields. The use of a sterically demanding directing group, such as 1-(2-pyridinylethyl)amine moiety, in amono-substituted aliphatic amides improved the yields of the products. The stoichiometric reaction of an amide with Ru3(CO)12 gave a stable di-nuclear ruthenium complex as a single ruthenium complex in which the 2-pyridinylmethylamino moiety is coordinated to the ruthenium center in a N,N-manner and an amide carbonyl oxygen binds to the other ruthenium center, but CeH bond activation is not involved. The complex itself does not show catalytic activity, but is activated in the presence of H2O under the catalytic reaction conditions employed. Ó 2013 Elsevier Ltd. All rights reserved.
Keywords: Ruthenium Catalysis Carbonylation CeH bond activation Chelation
1. Introduction The use of carbon monoxide (CO) in carbonyl reactions is one of the important methods for introducing carbonyl functionalities, such as acids, esters, lactones, amides, lactams, aldehydes, alcohols, and related functional groups both in the laboratory and on an industrial scale.1 A representative example involves the hydroformylation of propene (Oxo process), which, except for polymerization, is the largest industrial catalytic process. A wide variety of substrates have been used in carbonylation reactions reported. If CeH bonds, which are ubiquitous in organic molecules could be directly used in carbonylation reactions, it would provide a new possibility for exploring new types of atom economical reactions.2 In fact, surprisingly, CeH bonds were reported to participate in carbonylation a long time ago. To the best of our knowledge, the first effective example of the chelation-assisted carbonylation of CeH bonds was reported in 1955 by Murahashi,3 who carried out
* Corresponding author. Tel.: þ81 6 6879 7397; fax: þ81 6 6879 7396; e-mail address: [email protected] (N. Chatani). 0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tet.2013.02.006
the cobalt-catalyzed cyclocarbonylation of aromatic imines, which involves the carbonylation of C(sp2)eH bonds. The catalytic carbonylation of CeH bonds is an attractive method for the direct preparation of carbonyl compounds from aromatic compounds. In fact, Pd-catalyzed chelation-assistance systems have been used in the carbonylation of C(sp2)eH bonds.4,5 It was also found that Ru3(CO)12 catalyzes the regioselective carbonylation of CeH bonds in a variety of N(sp2)-containing compounds.6 However, compared with the extensively studied carbonylation of C(sp2)eH bonds,4e6 effective examples of the carbonylation of C(sp3)eH bonds were rare when we started this project.4g Tanaka reported on the Rhcatalyzed carbonylation of alkanes to produce aliphatic aldehydes under photo-irradiation conditions.7 Because of its endothermic nature, the reaction requires continuous photo-irradiation and alkanes must be used as the solvent. A wide variety of products are formed, including secondary products. We previously reported on the Rh-catalyzed carbonylation of C(sp3)eH bonds in amines.6k However, in this case, a nitrogen atom adjacent to the CeH bond was required for the carbonylation to proceed. Transition metal catalysis has recently emerged as a powerful tool for functionalizing C(sp2)eH bonds and a variety of transformations of C(sp2)eH
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bonds has already been developed. In this context, many groups have focused their attention on the functionalization of C(sp3)eH bonds, which is a more challenging topic.8 We recently reported on the development of N,N-bidentate directing group-assisted system9 in which a 2-pyridinylmethylamino group is used for the carbonylation of C(sp2)eH bonds in aromatic amides.10 In recent years, N,N-bidentate directing group systems have been used in the transformation of C(sp3)eH bonds.11 To broaden the scope of this approach, we applied the system to the carbonylation of C(sp3)eH bonds in aliphatic amides. We wish to report herein on the Rucatalyzed cyclocarbonylation of aliphatic amides through the regioselective activation of unactivated C(sp3)eH bonds.12
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11, was found to promote CeH bond carbonylation, but the yield of the corresponding carbonylation product was only 18%.
2. Results and discussion The reaction of amide 1a with CO and ethylene in the presence of Ru3(CO)12 in toluene at 160 C for 1 day gave the succinimide 2a in 22% yield, with 60% of 1a being recovered (Scheme 1). Running the reaction for 3 days resulted in an increase in product yield to 55%. Similar to the case of aromatic amides,10 ethylene, and H2O were found to have a positive effect on the outcome of the reaction. When the reaction was run in the absence of H2O, the yield of 2a decreased dramatically to 16%. The presence of ethylene is also crucial for the reaction to proceed, although it is not incorporated into the products. In fact, in the absence of ethylene, no carbonylation product was detected. The role of ethylene is not clear, but we speculate that it functions as a hydrogen acceptor. To test this hypothesis, other compounds, which are known to serve as hydrogen acceptors including norbornene, alkynes, and a,b-unsaturated carbonyl compounds were examined. When the ethylene was replaced with tert-butyl acrylate, the carbonylation product 2a was produced in 62% yield. After optimizing the reaction conditions, the following conditions were finally selected as standard reaction conditions: amide (1 mmol), CO (10 atm), ethylene (7 atm), H2O (2 mmol), Ru3(CO)12 (0.05 mmol), toluene (3 mL) as the solvent with the reaction run at 160 C for a period of 5 days.
Scheme 1. Carbonylation of unactivated C(sp3)eH bonds in amide 1a.
We next examined the effect of a directing group (Scheme 2). The reaction of N-4-pyridynylmethyl amide 3 did not result in the formation of the expected CeH bond carbonylation product, but, instead, 5 was formed in 94% yield. The reaction proceeds via two known, successive reactions: the Ru-catalyzed CeH bond carbonylation at the 2-position of pyridine leading to 46a and the Rucatalyzed [2þ2þ1] cycloaddition of the resulting pyridinyl ketones 4.13 No reaction occurred when the corresponding benzyl amide 6 was used as the substrate, in place of 1a, indicating that the coordination of the pyridine nitrogen to the catalyst is a key step for the reaction to proceed. Amides having shorter and longer carbon chains, such as 7 and 8 also did not give the corresponding imides. The oxazoline-based N,N-bidentate 914 and the N,S-bidentate system 1011e were also ineffective. An 8-aminoquinoline moiety, as in
Scheme 2. Effect of directing groups.
Table 1 shows some representative results for reactions of a,adi-substituted aliphatic amides under the standard reaction conditions. The carbonylation proceeded in highly regioselective manner. The reactions occurred exclusively at methyl CeH bonds, not at methylene CeH bonds, as shown in the reaction of 1b. Fivemembered ring formation occurred preferentially over sixmembered ring formation. Thus, the reaction of 1b gave a derivative of ethosuximide 2b, which is a succinimide anticonvulsant, that is, used mainly in the treatment of absence seizures, in 83% yield. Even when a methylene group is activated by the presence of a phenyl group, as in 1dek, or a methoxy group, as in 1l, methyl CeH bonds were selectively carbonylated. This selectivity can be attributed to steric factors. The reaction tolerated certain functional groups, such as MeO, Cl, CF3, CN, and even Br groups under the reaction conditions used. A sterically bulky aryl group, such as the pentamethylphenyl group, had no effect on the efficiency of the reaction. In the case of the cyclopropane substrate 1o, carbonylation of a methyl C(sp3)eH competed with that of the cyclopropane CeH bond, leading to a nearly 2:1 mixture of 12 and 2o.15 The carbonylation of CeH bonds in a benzene ring took place preferentially over the CeH bonds in a methyl group. Thus, the reaction of 1p gave 13 in 90% yield through C(sp2)eH bond activation, along with a small amount (<5%) of succinimide, which was formed through C(sp3)eH bond activation. As shown in the reaction of 1b, five-membered ring closing carbonylation occurred preferentially over six-membered ring closure. Even when 14 or 15 were used as the starting substrate, no corresponding six-membered carbonylation products formed. Even the presence of a nitrogen atom, cyclohexane CeH bonds as in 16 did not undergo the carbonylation.
While various a,a-di-substituted aliphatic amides underwent cyclocarbonylation in good yields under the current reaction
4468 Table 1 Carboylation of a,a-di-substituted aliphatic amidesa
N. Hasegawa et al. / Tetrahedron 69 (2013) 4466e4472 Table 1 (continued)
a
Reaction conditions: amide (1 mmol), CO (10 atm), ethylene (7 atm), H2O (2 mmol), Ru3(CO)12 (0.05 mmol), toluene (3 mL) at 160 °C for 5 days. b Isolated yields. c Toluene (4 mL). d Ru3(CO)12 (0.1 mmol) was used. conditions, as shown in Table 1, a a-mono-substituted aliphatic amide, such as isobutylic amide 1q gave the corresponding imide 2q in low yield, along with a variety of byproducts. This is probably because the cleavage of the C(O)eN bond in 1q took place under the reaction conditions. To avoid the cleavage of C(O)eN bonds, isobutylic amide, which contains a sterically bulky directing group, as in 1r was used as the substrate. As expected, an improved yield of 59% was obtained, but some unidentified byproducts were still produced. It was finally found that a methyl group, as in 1s is sufficiently bulky permit high yields of the product to be obtained. This newly developed directing group was applicable to other substrates, as in 1t, 1u, and 1v. While carbonylation did not take place at the methylene CeH bond in a cyclohexane ring, as in 1m (Table 1), the cyclobutane substrate 1v gave the corresponding carbonylation product 2v. The presence of a methyl or a phenyl group at the benzylic position improved the efficiency of the reaction of a-mono-substituted aliphatic amides, as shown in Table 2. This prompted us to examine the applicability of the new directing group in reactions of a,a-disubstituted aliphatic amides. If this directing group could be used, it would provide the opportunity to develop the enantioselective synthesis of succinimides using a chiral directing group. However, the observed diastereoselectivity was nearly 1:1, although the carbonylation products were obtained in good yields (Scheme 3). To gain insights into the mechanism of the reaction, deuterated 1m-CD3 was subjected to the reaction conditions with a low catalyst loading (5 mol %) to stop the reaction before it reached completion, in order to recover the starting amide (Scheme 4). Even at 68% conversion, no HeD exchange in the methyl group of the recovered starting amide 1m-CD3 was detected, indicating that the cleavage of the CeH bond is irreversible. In contrast, a significant amount of H/D exchange was observed at the methylene group a to the carbonyl group in product 2m. Because the methylene CeH bonds in 2m are acidic protons, H/D exchange between the CeH bonds and H2O readily took place under the reaction conditions
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and 1m-CD3. The results indicated that 1m reacts 1.8 times faster than 1m-CD3.
Table 2 Carbonylation of a-mono-substituted aliphatic amidesa
Scheme 4. Deuterium labeling experiment.
We next performed an intramolecular competitive experiment using 1d-(CH3)(CD3), in which the CeH bond reacts 3.8 times faster than CeD bond (Scheme 5).17 It was also found that that 1d is 3.6 times more reactive than 1d-(CD3)2 in an intermolecular competitive experiment. These results suggest that the cleavage of CeH bonds is the rate determining step in this new carbonylation reaction.
e
c,d
a
Reaction conditions: amide (1 mmol), CO (10 atm), ethylene (7 atm), H2O (2 mmol), Ru3(CO)12 (0.05 mmol), toluene (3 mL) at 160 °C for 5 days. b Isolated yields. A number in parenthesis is a diastereoisomeric ratio. c Ru3(CO)12 (0.15 mmol) was used. d 7 days. e Ru3(CO)12 (0.10 mmol) was used. employed. H/D Exchange at the methylene CeH bond in the 2pyridinylmethyl group also took place. The mechanism of the H/D exchange is not clear at the present time, it is well known that CeH bonds adjacent to a nitrogen atom can be activated.16 We next performed an intermolecular competition experiment using 1m Scheme 5. Competition experiments.
Scheme 3.
A stoichiometric reaction of amide 1a (0.02 mmol) with Ru3(CO)12 (0.007 mmol) was carried out in toluene at 130 C under N2, which resulted in the formation of the di-nuclear ruthenium complex 21, the structure of which was confirmed by X-ray crystallography (Fig. 1). Similar to the case of aromatic amides,10 the 2pyridinylmethylamine moiety is coordinated to the ruthenium center in an N,N-fashion and the carbonyl oxygen binds to the other ruthenium center. A proposed mechanism for the reaction, based on the results obtained, is shown in Scheme 6. A mono ruthenium species is proposed as a key catalytic species, although we were not able to collect any direct evidence for this. Coordination of a pyridine nitrogen in amide 1a to a ruthenium center followed by the oxidative
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suggests that this process has potential for exploring new types of CeH bond transformations that cannot be achieved when conventional chelation-assisted systems are used.9e12,19 4. Experimental section 4.1. General
Fig. 1. ORTEP drawing of 21.
addition of an NeH bond gives the ruthenium hydride complex 23. The insertion of ethylene, followed by irreversible CeH bond cleavage, gives ruthenacycle 25 with the simultaneous generation of ethane. The cleavage of the CeH bond probably takes place through s-bond metathesis of the complex 24.18 The insertion of CO and subsequent reductive elimination affords the final product, with the regeneration of the mono ruthenium species. The fact that no carbonylation product was formed in the absence of ethylene suggests that no direct cleavage of a CeH bond takes place in complex 23 and that ethylene functions as a hydrogen acceptor. The complex 21 does not participate in the main catalytic cycle but, rather, exists in a resting state. The presence of H2O is also important in terms of increasing the efficiency of the reaction, as shown in Scheme 1. The role of H2O appears to be to reduce the resting complex 21 by reduction, such as the water gas shift reaction19 to give the mono ruthenium species, which completes the catalytic cycle.
1 H NMR and 13C NMR spectra were recorded on a JEOL JNMEX270, JEOL JNM-ECS400, or VARIAN UNITY-INOVA600 spectrometer in CDCl3 with tetramethylsilane as the internal standard. Data are reported as follows: chemical shifts in parts per million (d), multiplicity (s¼singlet, d¼doublet, t¼triplet, q¼quartet, sept¼septuplicate, bs¼broad singlet, and m¼multiplet), coupling constant (Hertz), integration, and interpretation. Infrared spectra (IR) were collected on a Horiba FT-720 spectrometer; absorption. Mass spectra were obtained on Shimadzu GCMS-QP 2014 and Shimadzu GCMS-QP 5000 instruments with ionization voltages of 70 eV. Melting points were determined on a Yamato melting point apparatus and are uncorrected. Elemental analyses were performed by the Elemental Analysis Section of Osaka University. High resolution mass spectra (HRMS) were obtained on a JEOL JMS-DX303 instrument. Analytical gas chromatography (GC) was carried out on Shimadzu GC-14B, Shimadzu GC-2014, and Shimadzu GC-8A gas chromatographs, equipped with flame ionization detectors. Flash column chromatography was performed with SiO2 (Silicycle Silica Gel 60 (230e400 mesh)).
4.2. Typical procedure for carbonylation of amides (1) Ru3(CO)12 (32.5 mg, 0.05 mmol), N-(pyridin-2-ylmethyl)pivalamide (1a, 1 mmol), water (36 mL, 2 mmol), and toluene (3 mL) were placed in a 50-mL stainless steel autoclave under an atmosphere of nitrogen. After flushing the system with 7 atm of ethylene three times, it was pressurized to 7 atm and then with carbon monoxide to an additional 10 atm. The autoclave was heated in an oil bath at 160 C for 5 d. The autoclave was cooled to rt, and the excess CO and ethylene were released. After transferring the contents to a round-bottom flask with CHCl3, the reaction mixture was checked by NMR and GC analysis. The volatiles were removed in vacuo, and the residue was subjected to flash column chromatography on silica-gel (eluent; Hexane/EtOAc¼6/4) to give (2a) (172 mg, 79% yield based on 1a) as a yellow oil. Distillation in vacuo gave a colorless oil. 4.3. Characterization data
Scheme 6. Proposed mechanism.
3. Conclusion In conclusion, we report on a new method for the carbonylation of unactivated C(sp3)eH bonds. The reaction of aliphatic amides with CO in the presence of Ru3(CO)12 gave cyclocarbonylation products. The presence of a 2-pyridynylmethylamino moiety, as an N,N-bidentate directing group in the substrates is crucial for the success of the reaction. The reaction proceeds selectively at a methyl CeH bond over a methylene CeH bond. The reaction tolerates a variety of functional groups. The carbonylation of C(sp3)eH bonds was achieved by the presence of N,N-bidentate directing group. This
4.3.1. 1-(1-(Pyridin-2-yl)ethyl)pyrrolidine-2,5-dione (2s). Colorless oil. Rf¼0.17 (Hexane/EtOAc¼1/1). 1H NMR (400 MHz, CDCl3): d 1.34 (dd, J¼10.0, 7.2, 3H), 1.82 (d, J¼6.8, 3H), 2.30e2.39 (m, 1H), 2.81e2.98 (m, 2H), 5.46 (q, J¼7.2, 1H), 7.16 (dd, J¼4.8, 7.2, 1H), 7.35 (d, J¼8.0, 1H), 7.66 (dt, J¼1.6, 8.0, 1H), 8.52 (d, J¼4.4, 1H). 13C NMR (100 MHz, CDCl3): d 15.73, 15.82, 16.72, 34.44, 34.50, 36.34, 50.80, 50.86, 120.60, 120.67, 122.11, 136.35, 136.37, 149.04, 158.10, 176.23, 180.37. IR (neat): 3456 w, 1774 m, 1704 s, 1591 s, 1572 w, 1471 m, 1435 m, 1396 s, 1363 s, 1292 m, 1228 m, 1120 s, 1153 w, 1122 m, 1078 w, 1041 m, 1016 w, 993 w, 947 w, 916 w, 883 w, 802 m, 773 m, 750 m, 690 w, 607 w. MS, m/z (relative intensity, %): 218 (Mþ, 18), 106 (100), 79 (34), 78 (16). HRMS: calcd for C12H14N2O2: 218.1055. Found: 218.1062. 4.3.2. 3-Benzyl-1-(1-(pyridin-2-yl)ethyl)pyrrolidine-2,5-dione (2t). Colorless oil. Rf¼0.14 (Hexane/EtOAc¼1/1). 1H NMR (399.78 MHz, CDCl3): d 1.74e1.78 (m, 3H), 2.45e2.52 (m, 1H), 2.67e2.78 (m, 1H), 2.89e3.00 (m, 1H), 3.11e3.21 (m, 1H), 5.44 (qd, J¼7.2, 7.2, 1H), 7.14e7.20 (m, 3H), 7.23e7.31 (m, 4H), 7.60e7.67 (m, 1H), 8.51e8.53
N. Hasegawa et al. / Tetrahedron 69 (2013) 4466e4472
(m, 1H). 13C NMR (100.53 MHz, CDCl3): d 15.68, 15.79, 33.05, 33.11, 36.31, 36.37, 40.93, 41.00, 50.95, 51.03, 120.65, 120.75, 122.17, 122.19, 126.96, 128.74, 129.13, 129.23, 136.41, 136.43, 137.01, 137.11, 149.12, 158.03, 176.10, 179.04. IR (neat): 1774 m, 1703 s, 1590 w, 1541 w, 1495 w, 1473 w, 1437 w, 1392 s, 1363 m, 1290 w, 1228 w, 1194 m, 1155 w, 1111 w, 1036 w, 995 w, 960 w, 920 w, 883 w, 802 w, 775 w, 750 m, 704 m, 607 w. MS, m/z (relative intensity, %): 295 (11), 294 (Mþ, 53), 293 (26), 203 (19), 121 (15), 117 (26), 115 (15), 107 (61), 106 (100), 91 (40), 79 (26), 78 (22), 65 (12), 55 (11). HRMS: calcd for C18H18N2O2: 294.1368. Found: 294.1366. 4.3.3. 3-(1-(Pyridin-2-yl)ethyl)-3-azabicyclo[3.1.0]hexane-2,4-dione (2u). White solid. Mp: 65.5 C. Rf¼0.17 (Hexane/EtOAc¼1/1). 1H NMR (400 MHz, CDCl3): d 1.47e1.52 (m, 1H), 1.64e1.67 (m, 1H), 1.77 (d, J¼7.6, 3H), 2.43e2.51 (m, 2H), 5.25 (q, J¼7.2, 1H), 7.15 (dd, J¼4.8, 7.2, 1H), 7.32 (d, J¼8.0, 1H), 7.66 (dt, J¼1.6, 8.0, 1H), 8.50 (d, J¼5.2, 1H). 13C NMR (100 MHz, CDCl3): d 16.09, 19.95, 20.09, 20.16, 49.92, 120.54, 122.14, 136.44, 149.07, 158.26, 175.03, 175.12. IR (KBr): 1772 w, 1705 s, 1591 w, 1572 w, 1473 w, 1435 w, 1387 m, 1356 m, 1188 w, 1043 w, 997 w, 949 w, 908 w, 858 w, 827 w, 804 w, 781 w, 764 w, 642 w, 609 w. MS, m/z (relative intensity, %): 216 (Mþ, 41), 147 (12), 121 (45), 120 (18), 119 (10), 107 (10), 106 (100), 105 (16), 104 (14), 95 (13), 93 (15), 79 (37), 78 (34), 70 (10), 68 (24), 55 (10), 52 (14), 51 (2). 4.3.4. 3-(1-(Pyridin-2-yl)ethyl)-3-azabicyclo[3.2.0]heptane-2,4dione (2v). Pale brown oil. Rf¼0.37 (EtOAc). 1H NMR (399.78 MHz, CDCl3): d 1.87 (d, J¼7.2 Hz, 3H), 2.16e2.32 (m, 2H), 2.58e2.72 (m, 2H), 3.26e3.32 (m, 2H), 5.52 (q, J¼7.2 Hz, 1H), 7.17 (dd, J¼8.0, 4.0 Hz, 1H), 7.39 (d, J¼8.0 Hz, 1H), 7.68 (td, J¼8.0, 1.6 Hz, 1H), 8.53 (d, J¼4.4 Hz, 1H). 13C NMR (100.53 MHz, CDCl3): d 15.71, 22.92, 23.12, 38.14, 38.21, 50.62, 120.59, 122.12, 136.45, 149.10, 158.28, 179.75, 179.83. IR (ATR): 2989 w, 2948 w, 2361 w, 2340 w, 1767 w, 1692 s, 1591 w, 1572 w, 1472 w, 1435 w, 1379 m, 1357 m, 1296 w, 1242 w, 1183 m, 1119 w, 1089 w, 1034 w, 992 w, 957 w, 927 w, 868 w, 801 w, 784 w, 762 w, 747 w. MS, m/z (relative intensity, %): 230 (Mþ, 47), 121 (25), 107 (11), 106 (100), 105 (17), 93 (13), 79 (29), 78 (23), 70 (10), 55 (14), 54 (14), 53 (16), 51 (11). HRMS: calcd for C13H14N2O2: 230.1055. Found: 230.1057. 4.3.5. 3-Benzyl-3-methyl-1-(1-(pyridin-2-yl)ethyl)pyrrolidine-2,5dione (18). Colorless oil. Rf¼0.23 (Hexane/EtOAc¼1/1). 1H NMR (399.78 MHz, CDCl3): d 1.39e1.43 (s, 3H), 1.61e1.69 (d, J¼7.4 Hz, 3H), 2.34e2.43 (d, J¼18.4 Hz, 1H), 2.68 (d, J¼13.2 Hz, 1H), 2.77e2.80 (d, J¼18.4 Hz, 1H), 3.19e3.20 (d, J¼13.2 Hz, 1H), 5.30e5.38 (q, J¼7.4 Hz, 1H), 6.98e7.19 (m, 4H), 7.24e7.26 (m, 3H), 7.55e7.61 (t, J¼7.6 Hz, 1H), 8.48, 8.50 (d, J¼4.4 Hz, 1H). 13C NMR (100.53 MHz, CDCl3): d 15.40, 15.64, 25.43, 39.35, 39.45, 43.22, 43.25, 44.58, 44.74, 50.76, 50.83, 120.32, 120.61, 121.98, 122.04, 127.05, 128.49, 128.52, 129.92, 130.04, 136.07, 136.29, 148.92, 149.01, 157.98, 158.03, 175.38, 175.45, 181.95, 182.02. IR (neat): 1774 m, 1701 s, 1591 m, 1574 w, 1495 w, 1471 m, 1454 m, 1437 m, 1394 s, 1363 s, 1288 w, 1255 w, 1228 w, 1198 s, 1153 w, 1095 w, 1074 w, 1030 w, 995 w, 957 w, 916 w, 864 w, 800 w, 768 m, 748 m, 706 m, 602 w. MS, m/z (relative intensity, %): 308 (Mþ, 28), 307 (16), 294 (17), 293 (77), 217 (12), 117 (27), 115 (12), 107 (23), 106 (100), 91 (81), 79 (20), 78 (19), 69 (10), 65 (12). HRMS: calcd for C19H20N2O2: 308.1525. Found: 308.1523. 4.3.6. 3-Benzyl-3-methyl-1-(phenyl(pyridin-2-yl)methyl)pyrrolidine-2,5-dione (20). Colorless oil. Rf¼0.31 (Hexane/EtOAc¼1/1). 1H NMR (399.78 MHz, CDCl3): d 1.41 1.43 (s, 3H), 2.38e2.42 (d, J¼18.0 Hz, 1H), 2.67e2.69 (d, J¼13.6 Hz, 1H), 2.79e2.80 (d, J¼18.0 Hz, 1H), 3.19e3.20 (d, J¼13.2 Hz, 1H), 6.45e6.47 (s, 1H), 6.89e7.06 (m, 3H), 7.13e7.31 (m, 9H), 7.51e7.56 (m, 1H), 8.50e8.54 (m, 1H). 13C NMR (100.53 MHz, CDCl3): d 25.48, 25.54, 39.33, 39.43, 42.95, 43.10, 44.74, 44.84, 59.50, 59.74, 122.04, 122.14, 122.41, 122.85, 126.89, 126.95, 127.94, 128.09, 128.39, 128.44, 128.48,
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129.10, 129.65, 129.95, 130.00, 135.99, 136.08, 136.52, 136.57, 149.02, 149.04, 156.52, 156.81, 175.27, 175.41, 181.89, 182.07. IR (neat): 1776 m, 1709 s, 1589 m, 1495 m, 1456 m, 1435 m, 1390 s, 1362 s, 1255 w, 1188 m, 1153 m, 1124 w, 1078 w, 997 w, 912 m, 791 w, 733 m, 702 s, 633 w, 611 w, 586 w. MS, m/z (relative intensity, %): 370 (Mþ, 2.9), 168 (20), 167 (100), 91 (19), 79 (29). HRMS: calcd for C24H22N2O2: 370.1681. Found: 370.1682. Acknowledgements This work was supported, in part, by a Grant-in-Aid for Scientific Research on Innovative Areas ‘Molecular Activation Directed toward Straightforward Synthesis’ from The Ministry of Education, Culture, Sports, Science and Technology. References and notes 1. For reviews on carbonylation, see: Colquhoun, H. M.; Thompson, D. J.; Twigg, M. V. Carbonylation: Direct Synthesis of Carbonyl Compounds; Plenum: New York, NY, 1991. 2. For recent reviews on functionalization of CeH bonds, see: (a) Kakiuchi, F.; Kochi, T. 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13. Chatani, N.; Tobisu, M.; Asaumi, T.; Fukumoto, Y.; Murai, S. J. Am. Chem. Soc. 1999, 121, 7160; Tobisu, M.; Chatani, N.; Asaumi, T.; Akamo, K.; Ie, Y.; Fukumoto, Y.; Murai, S. J. Am. Chem. Soc. 2000, 122, 12663. See also Ref. 4g. 14. Giri, R.; Maugel, N.; Foxman, B. M.; Yu, J.-Q. Organometallics 2008, 27, 1667. 15. In the Pd-catalyzed carbonylation reaction of C(sp3)eH bonds, cyclopropane CeH bonds are selectively carbonylated. See Ref. 4g. 16. Campos, K. R. Chem. Soc. Rev. 2007, 36, 1069. 17. Similar to the case of 2m, H/D exchange at the CH2 group a to the carbonyl group and at the CH2 group in 2-pyridinylmethyl group was also observed in the carbonylation product. 18. Hartwig, J. F. Organotransition Metal Chemistry; University Science Books: Mill Valley, CA, 2010; p 285. 19. Quite recently, we reported the Ru(II)-catalyzed arylation of the ortho CeH bonds in aromatic amides through a bidentate directing system: Aihara, Y.; Chatani, N. Chem. Sci. 2013, 4, 664.