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Palladium-Catalyzed Intramolecular Hydroaminocarbonylation to Lactams: Additive-Free Protocol Initiated by Palladium Hydride Yue Hu, Zhiqiang Shen, and Hanmin Huang ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b01939 • Publication Date (Web): 08 Sep 2016 Downloaded from http://pubs.acs.org on September 9, 2016
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Palladium-Catalyzed Intramolecular Hydroaminocarbonylation to Lactams: Additive-Free Protocol Initiated by Palladium Hydride Yue Hu†§, Zhiqiang Shen†, and Hanmin Huang*,†,‡ †
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou, 730000, P. R. China ‡
Department of Chemistry, University of Science and Technology of China, Hefei, 230026, P. R. China
§
University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
ABSTRACT: A palladium-catalyzed intramolecular hydroaminocarbonylation of 2-vinylbenzylamines in the absence of acidic or any other additives was realized via rational designing the catalytic system on the basis of mechanistic studies, which allows for the synthesis of a variety of six-membered lactams in good to excellent yields with high regioselectivity. The postulated palladium-hydride intermediate for initiating the hydroaminocarbonylation has been identified and directly used as catalyst for the reaction. Further kinetic studies illustrated that the reaction rate is negative first-order dependent on the substrate concentration with palladium hydride as catalyst. KEYWORDS: intramolecular hydroaminocarbonylation • palladium hydride • aliphatic amine • lactam • homogeneous catalysis
A
mides represent one of the most commonly encountered classes of reagents in synthetic organic chemistry.1 The broad spectrum of amide has spurred extensive efforts toward the development of efficient methods to prepare these compounds and related derivatives from simple precursors.2 Among the most direct and general approaches for synthesizing amides is the Pdcatalyzed hydroaminocarbonylation of simple alkenes with amines in the presence of CO.3-4 Although 100% atom-economy could be achieved, the development of such a process, however, is complicated by several factors, including the basicity barrier imparted by the strong basic aliphatic amines and regioselectivity of the products.3g As a result, acidic additives as well as special ligands were generally required to achieve the catalyst turnover and high selectivity. In considering basic design criteria, an optimal process would enable the hydroaminocarbonylation reaction to be proceeded under mild reaction conditions in the absence of additives. The intramolecular hydroaminocarbonylation of amino alkenes in the presence of CO provided a direct and atom-economy approach to lactams, which represented an ubiquitous structural motifs widely found in many natural alkaloids and biologically active compounds.5 In this context, Alper and co-workers developed an elegant Pd-catalyzed selective intramolecular hydroaminocarbonylation of 2-vinylanilines and 2-allylanilines for the synthesis of a series of five-, six- or seven-membered lactams in the presence of CO/H2.6 Although this reaction could proceed with high chemoselectivity and regioselectivity controlled by the phosphine ligands and catalyst precursor, the substrates were still restricted to aromatic amine moiety as the intramolecular coupling partner. Furthermore, to achieve the catalytic turnover, the hydrogen gas (H2) was required to facilitate the generation of the postulated key palladium hydride species for initiating the reaction,
which restricted the practicality of this process. These results promoted us to explore an alternative strategy to circumvent the aforementioned problems and elucidate how the postulated palladium hydride species influence these reactions.7 Herein, we described the development of the first palladium-catalyzed intramolecular hydroaminocarbonylation of 2-vinylbenzylamines in the absence of acidic additives or hydrogen gas, which allowed for the synthesis of a variety of six-membered lactams in good to excellent yields with high selectivity. The postulated palladium hydride has been identified for the first time. Isotopic labelling experiments and kinetic studies elucidated that the reaction rate is negative first-order dependent on the substrate concentration. Scheme 1. Palladium-catalyzed intramolecular hydroaminocarbonylation of 2-vinylbenzylamines.
The postulated catalytic cycle shown in Scheme 1 suggested that the hydroaminocarbonylation of 2-vinylbenzylamine initiated by palladium hydride could be realized through manipulation of the delicate balance of the two types of reaction between the palladium hydride species and 2-vinylbenzylamine 1 (reductive elimination vs hydropalladation).8 Initially, the resting state HPd(PR3)2Cl would undergo a reversible dissociation of PR3 before a turnover limiting step. Then the hydroaminocarbonylation
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initiated by palladium hydride would be furnished via hydropalladation, CO insertion and aminolysis.3d Since only the aminolysis is an irreversible step, the off-cycle competitive reductive elimination of H-Pd-X to Pd(0) promoted by amine 1 would be suppressed by speeding up the aminolysis step. On the basis of this consideration, we reasoned that the intramolecular hydroaminocarbonylation might be accomplished in the absence of acidic additives since the intramolecular aminolysis step is much faster than that of intermolecular reaction. However, to the best of our knowledge, no example has been reported on intramolecular hydroaminocarbonylation with more basic aliphatic amines as coupling partners in the absence of acidic or any other additives. Scheme 2. Stoichiometric reaction of unsaturated amine 1a with Pd-D species
To validate our hypothesis, the hydroaminocarbonylation of Nbenzyl-1-(2-vinylphenyl)methanamine (1a), which contains more basic aliphatic amino moiety, was conducted with stoichiometric DPd(t-Bu3P)2Cl (76%D) in the presence of 20 atm of CO in THF at 120oC (the structure of HPd(t-Bu3P)2Cl was confirmed by Xray analysis, see Supporting Information).8-9 The reaction underwent smoothly to give the desired lactam d-2a in 83% yield and the content of deuterium in the corresponding product d-2a caused only slight loss at methyl position (60%D) and 8% deuteration incorporation occurred at methine position through 1H NMR analysis (Scheme 2). This result indicated that the palladium hydride was indeed involved in the present reaction and the hydropalladation was reversible. Further investigation demonstrated that over 90% yield was obtained when the reaction was conducted under the catalysis of HPd(t-Bu3P)2Cl.
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was employed in the catalytic reaction, no desired product 2a was observed during the first half an hour and the rate rose slowly even in the next six hours. In sharp contrast to the lower catalytic activity of Pd(t-Bu3P)2, HPd(t-Bu3P)2Cl shown higher activity for promoting the catalytic reaction and no inductive period was observed, which further comfirmed that the reaction was indeed initiated by palladium hydride species. Further circumstantial evidence for supporting the reaction triggered by palladium hydride species came from the reaction profile catalyzed by Pd(PPh3)2Cl2. A longer inductive time was observed which suggested that the Pd(PPh3)2Cl2 had to be converted to palladium hydride to catalyze the reaction. Stimulated by the above observations, the initial rate of the reaction catalyzed by HPd(t-Bu3P)2Cl was measured by varying the concentration of the substrate 1a [0.25-0.45 M] and keeping the concentration of HPd(t-Bu3P)2Cl on 0.01M. As illustrated in Figure 2, the reaction rate of the carbonylation was negative first-order dependence on the concentration of substrate 1a, which was in agreement with our hypothesis that the palladium hydride could be consumed by the off-cycle reductive elimination under the higher concentration of 1a due to the strong basicity of aliphatic amine moiety contained in 1a.
Figure 2. Plot of initial rates (kobs) with respect to substrate [1a] showing negative first-order dependence; 1a (0.25-0.45 M), [HPd(t-Bu3P)2Cl] = 0.01 M, THF (1 mL), 120 oC, CO (20 atm).
Figure 1. Reaction profiles of hydroaminocarbonylation of 2vinylbenzylamine 1a catalyzed by different Pd species. Reaction conditions: 1a (0.2 mmol), [Pd] (5 mol%), THF (1 mL), 120 oC, CO (20 atm). The yield of product 2a was determined by GC with n-hexadecane as the internal standard.
To further disclose how the palladium hydride influences the reaction process, some kinetic investigations of this intramolecular hydroaminocarbonylation with different catalyst precursors were then conducted. As shown in Figure 1, when Pd(t-Bu3P)2
These results intrigued us to investigate the viability of this hydroaminocarbonylation reaction on the basis of our mechanistic studies. As shown in Table 1, 91% isolated yield was obtained when the reaction was conducted in the presence of 20 atm of CO with Pd(PPh3)Cl2 as catalyst. No desired product 2a was detected when the commonly used PdCl2 and Pd(OAc)2 were utilized as catalysts (Table 1, entry 2-3). It is the same as Pd(t-Bu3P)2 that the zero-valent Pd(PPh3)4 could not catalyze the present reaction, and only trace amount of 2a was observed (Table 1, entry 4). Furthermore, the diphosphine Xantphos ligated palladium catalysts Pd(Xantphos)Cl2 and Pd(Xantphos)(CH3CN)2(OTf)2 could also promote the desired reaction to get product 2a in relatively lower yield (Table 1, entries 5-6). Finally, control reaction demonstrated that no product 2a was observed in the absence of palladium catalyst (see Supporting Information). Since the Pd(PPh3)2Cl2 is much more stable and inexpensive than HPd(tBu3P)2Cl, we chose it as the best catalyst. After Pd(PPh3)2Cl2 was identified as the best catalyst, the other reaction parameters were then investigated. Apart from THF, the reaction could also be conducted well in toluene and dioxane to deliver the desired product 2a in good to excellent yields (entries 7-8). Then protic solvents were tested, and MeOH was found to be the most effective which the desired product 2a could be isolated in 96% yield (entry 10). Subsequently, the effect of temperature was also screened. When the temperature decreased from 120 oC to 100 oC, the yield of 2a was sharply dropped to 59% (entry 11). Trace amount of 2a was detected when we further lowered the tempera-
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ture to 80 oC (entry 12). Furthermore, when we shorten the reaction time to 12 hours, almost the same yield of product 2a was achieved (entry 13). However, further decreasing the reaction time to 6 hours resulted in lower conversion (entry 14). It was worth noting that the reaction also proceeded well when we reduce the pressure of CO to 10 atm (see Supporting Information).
Table 2. Substrate scope a
Table 1.Optimization of the reaction conditionsa
entry
[Pd]
solvent
T(oC)
1 2 3 4 5
Pd(PPh3)2Cl2 PdCl2 Pd(OAc)2 Pd(PPh3)4 Pd(Xantphos)Cl2 Pd(Xantphos)(C H3CN)2(OTf)2 Pd(PPh3)2Cl2 Pd(PPh3)2Cl2 Pd(PPh3)2Cl2 Pd(PPh3)2Cl2 Pd(PPh3)2Cl2 Pd(PPh3)2Cl2 Pd(PPh3)2Cl2 Pd(PPh3)2Cl2
THF THF THF THF THF
120 120 120 120 120 120
6 7 8 9 10 11 12 13 14
THF toluene dioxane EtOH MeOH MeOH MeOH MeOH MeOH
120 120 120 120 100 80 120 120
Time (h) 24 24 24 24 24
Yield (%)b 91 NR NR trace 50
24
34
24 24 24 24 24 24 12 6
80 88 90 96 59 trace 95 66
a
Reaction conditions: 1a (0.5 mmol), [Pd] (0.025 mmol), solvent (1.0 mL), CO (20 atm). bIsolated yield. Bn=benzyl.
With the optimized conditions in hand, a wide range of 2vinylbenzylamines 1 were examined for its generality. As shown in Table 2, the distinct substituents on the aromatic ring of the substrates demonstrated that electronic properties did not have a strong influence on the reactivity. For instance, the reaction of substrates with electron-donating groups such as 5-methyl, 4methyl and substrates with electron-withdrawing groups like 5fluoro, 5-chloro all proceeded in good to excellent yields under standard conditions (2b-2e). Notably, the synthesis of 2d with an intact chlorine on aromatic ring indicated the good tolerance of this reaction condition and provided the opportunity for further transformation by transition-metal-catalyzed C-C or C-X bond formation reaction. The substituent on nitrogen atom of 1a was also compatible with the present catalytic system. The reactions underwent smoothly for the substrates with electron-rich groups located on the nitrogen atom (1f, 1g, 1h), affording the corresponding lactams in 69-90% yields. However, when substrates with electron-deficient groups like 1i, 1j and 1k were treated with CO under the same conditions with MeOH as solvent (Table 1, entry 13), the intermolecular hydroesterification products instead of the hydroaminocarbonylation products were obtained (see Supporting Information). This phenomenon might lie in the weakened nucleophilic ability of their nitrogen atoms. Replacing MeOH with THF as solvent, the corresponding intramolecular hydroaminocarbonylation reactions took place to give the corresponding lactams 2i, 2j and 2k in 68-98% yields. Interestingly, substrate 1l without any substituents on nitrogen atom could also be tolerated in this reaction and afforded the corresponding product 2l in 67% yield. Subsequently, substrates bearing different substituents at the β-position of the vinyl group have been screened, affording
a
Reaction conditions: 1 (0.5 mmol), Pd(PPh3)2Cl2 (5 mol%), MeOH (1 mL), CO (20 atm), 120 oC, 12 h, isolated yields are shown unless otherwise noted. b24 h. cPd(PPh3)2Cl2 (10 mol%), 140 oC, 24 h. d140 oC, 24 h. e 140 oC, 48 h. fTHF was used as solvent instead of MeOH. gThe ratio of d.r. was determined by GC-MS analysis of the crude product.
the corresponding lactams 2m and 2n in 79% and 62% yields respectively albeit prolonged reaction time and higher temperature were required. Seven-membered cyclocarbonylation product 2o was obtained in only 26% yield when substrate 1o with a methyl group at the α-position of the vinyl moiety. In addition, substrate 1p with a methyl at the α-position of amine could be easily converted into the desired product 2p in 72% yield (d.r.=1.2:1). Next, if we replaced methyl group at α-position of the amine with carbonyl group, the reaction proceeded smoothly to provide the desired product 2q in 94% yield. Notably, substrate 1r bearing a hydroxyl group at nitrogen atom, affording the unexpected product 2r in moderate yield, in which the N-O bond was cleaved. Finally, the ring-fused lactone was also successfully obtained in 84% yield when 2-vinylbenzylalcohol was employed as a substrate. The structures of 2h, 2o and 2r were confirmed by X-ray single-crystal diffraction analysis.9
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To gain some insight into the origin of the palladium hydride species, several experiments were carried out under the optimized conditions. As depicted in Scheme 3, the transformation of 1a to 2a was initially performed with ultra-dry toluene as the solvent,10 and product 2a was still isolated in 83% yield which might ruled out the possibility that the palladium hydride produced from the trace amount of water in solvent (Scheme 3, eq 1). Then deuterium-labeled substrates d2-1h and d2-1a' were synthesized and utilized in this reaction. The desired products d2-2h and d2-2a' were obtained almost no deuterium loss (Scheme 3, eq 2 and eq 3). These results suggested that the palladium hydride most likely generated from the palladium (II) precatalysts by the attack of benzylamine on a coordinated double bond and β-hydrogen elimination from the resulting aminoalkyl intermediate.11 Scheme 3. Preliminary studies on the origin of the Pd-H species
In summary, we have identified, for the first time, the postulated palladium hydride in the catalytic cycle of hydroaminocarbonylation and disclosed that the reaction rate is negative firstorder dependent on the substrate concentration with palladium hydride as catalyst, furnishing a possible rationalization for the observed substrate inhibited. On the basis of these findings, an efficient palladium-catalyzed intramolecular hydroaminocarbonylation of 2-vinylbenzylamines in the absence of acidic additive or any other promoters has been established, which allows for the synthesis of a wide range of biologically active benzene-fused lactams. Further investigations aimed at gaining a detailed mechanistic understanding of this reaction and developing enantioselective hydroaminocarbonylation by using this strategy are currently underway.
ASSOCIATED CONTENT Supporting Information Experimental details and full spectroscopic data for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION Corresponding Author *E-mail:
[email protected] Notes The authors declare no competing financial interest.
ACKNOWLEDGMENT
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This research was supported by the CAS Interdisciplinary Innovation Team, the National Natural Science Foundation of China (21133011, 21672199).
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(i) Gauthier, D.; Lindhardt, A. T.; Olsen, E. P. K.; Overgaard, J.; Skrydstrup, T. J. Am. Chem. Soc. 2010, 132, 7998-8009. (j) Fujihara, T.; Katafuchi, Y.; Iwai, T.; Terao, J.; Tsuji, Y. J. Am. Chem. Soc. 2010, 132, 2094-2098. (8) For studying on the reductive elimination of HPdX promoted by amine, see: Hills, I. D.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 13178-13179. (9) CCDC 1485974 (2h), 1485976 (2o), 1485973 (2r) and 1485977 (HPd(t-Bu3P)2Cl) contain the supplementary crystallographic data for this paper. This data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. (10) Ultra-dry toluene was purchased from Sigma-Aldrich. Almost the same reactivity was observed in the wet THF and dry THF (see Supporting Information for details). (11) (a) Nettekoven, U. Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 1166-1167. (b) Hartwig, J. F. Pure Appl. Chem. 2004, 76, 507-516.
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