DOI: 10.1002/chem.201500779
Communication
& Aminocarbonylation
Palladium-Catalyzed Aminocarbonylation of N-Chloroamines with Boronic Acids Wanfang Li and Xiao-Feng Wu*[a] dition to the C X bond carbonylation reactions, the investigation of carbonylative transformation of N X bonds is of interest to both academic and industrial researchers. However, this transformation (Scheme 1 b) remains unknown in the literature. The use of N X-based substrates in metal-catalyzed cross-coupling reactions has recently been described.[4] Compared with C X-based coupling reactions, these transformations proceeded under milder conditions and tolerated a wider array of functional groups, due to the high and varied reactivity of N X bonds.[5] In light of all of these developments, we became interested in developing an N X bond-based carbonylation reaction. Based on the widely accepted mechanism of palladium-catalyzed carbonylative cross-coupling between aryl halides and amines,[3] we envisioned that an electrophilic aminocarbonylation reaction is conceptually viable (Scheme 2). Firstly, the oxi-
Abstract: Aryl (pseudo)halide-based (C X) carbonylation reactions have been extensively studied during the past few decades. From both academic and synthetic points of view, the carbonylative transformation of N X bonds represents an interesting and attractive area of investigation. In light of this, the first carbonylative cross-coupling between N-chloroamines and organoboronic acids has been developed. This new type of aminocarbonylation proceeds at mild temperatures (45–55 8C) with 2 mol % Pd/C (10 wt %) as the ligand-free catalyst. Not only arylboronic acids, but also alkenyl- and alkylboronic acids can be applied as the substrates and bromide and iodide substituents in the substrates are well tolerated. Initial mechanistic investigations have also been performed.
Palladium-catalyzed aminocarbonylation of aromatic and alkenic (pseudo)halides (C X bonds), which was first reported by Schoenberg and Heck in 1974,[1] has since evolved into a powerful and reliable tool for amide bond formation (Scheme 1 a).[2] Typically, these reactions are initialized by the oxidative addition of C(sp2) X bonds onto Pd0 precatalysts. The ensuing CO insertion, nucleophilic attack, and reductive elimination steps contribute to the whole catalytic cycle.[3] In all of these traditional aminocarbonylation reactions, C(sp2) X species have acted as the electrophile and amines as the nucleophile. In ad-
Scheme 2. Proposed catalytic cycle of electrophilic aminocarbonylation.
dative addition of N O[6] and N Cl[7] bonds to Pd0 species has been proposed in hetero-Heck reactions with some preliminary evidence. In view of the unprecedented, possibly quite difficult, CO insertion into palladium–amide bonds,[8] that is, the formation of intermediate C’ (Scheme 2), we presumed that transmetallation proceeded before CO insertion, whereby the acyl PdII intermediate C, rather than the aryl carbamoyl PdII intermediate D’, would form.[3b] In the final reductive elimination step, the product was released and Pd0 was regenerated. To implement the above ideas, we embarked on our experiments with phenylboronic acid (1 a) and N-chloropiperidine (2 a), which could be easily prepared by chlorination of piperidine with aqueous sodium hypochlorite.[9] Initially, we carried out the reaction with 3 mol % [Pd(PPh3)4], two equivalents of 2 a, and K2CO3 as the base in THF, which afforded benzoyl pi-
Scheme 1. Carbonylation procedures: a) C X bond-based carbonylation; b) N X bond-based carbonylation.
[a] Dr. W. Li, Prof. Dr. X.-F. Wu Leibniz-Institut fr Katalyse e.V. an der Universitt Rostock Albert-Einstein-Strasse 29 a, 18059 Rostock (Germany) E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201500779. Chem. Eur. J. 2015, 21, 1 – 6
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Communication Table 1. Selected optimization of the carbonylative cross-coupling between 1 a and 2 a.[a]
Table 2. Selected optimization of the reaction conditions using in situgenerated N-chloropiperidine.[a]
Entry
Pd (mol %)
Base (equiv)
Solvent
Yield [%]
1[c] 2[c] 3[c] 4[c] 5 6 7 8 9 10 11 12[d]
[Pd(PPh3)4] (3) [Pd2(dba)3] (3) Pd(OAc)2 (3) PdCl2 (3) Pd/C (2) Pd/C (2) Pd/C (2) Pd/C (2) Pd/C (4) Pd/C (4) Pd/C (4) Pd/C (2)
K2CO3 (2) K2CO3 (2) K2CO3 (2) K2CO3 (2) NaHCO3 (2) NaHCO3 (2) NaHCO3 (3) NaHCO3 (3) NaHCO3 (3) Na2CO3(3) NaOAc (3) NaHCO3 (3)
THF THF THF THF dioxane toluene DME MTBE MTBE MTBE MTBE MTBE
24 21 13 29 33 27 21 48 66 32 41 69 (26[e])
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y [bar]
T [8C]
Yield [%][b]
1 2 3 4 5 6 7 8
2 2 2 3 3 3 3 3
50 40 50 50 50 80 50 50
40 35 45 45 60 45 45 45
66 (46[c]) 33 67 (0[d]) 73 (70[e]) 71 81 41[f] 0[g]
base amount, reaction temperature and CO pressure led to a much higher yield of 3 a, if CO pressure is 80 bar (81 %, Table 2, entry 6). Much like the reactions with with preformed N-chloropiperidine, other homogeneous palladium precursors, such as [Pd(PPh3)4], Pd(dba)2 and Pd(OAc)2, were again much less effective for this reaction (see the Supporting Information, Table S2). Other N-halogenation reagents, TCCA (trichloroisocyanuric acid) and NBS (N-bromosuccinimide), were much less reactive than NCS (Table 2, entry 7 and 8). Importantly, no formation of 3 a was detected when NCS was replaced with oxidants such as BQ (benzoquinone), DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone), K2S2O4, tBuOOtBu, or tBuOOH (see the Supporting Information, Table S3). These results can rule out the occurrence of the usual oxidative carbonylation process.[10] To gain further mechanistic insight into the reaction, several control experiments were carried out. In all of the above optimization reactions, and even in the absence of CO gas, we detected no N-phenylpiperidine (4 a, Scheme 3), which would likely be produced from the reductive elimination of intermediate B in Scheme 2.[4a] During the optimization process, we also observed that carbamoyl chloride (5 a) and urea were produced as byproducts in some cases. Specifically, piperidine-1-carbonyl chloride 5 a was obtained in 87 % GC yield when no base was added (Scheme 4 a). Nevertheless, carbamoyl chloride did not undergo cross-coupling with phenylboronic acid (1 a) under our con-
peridine 3 a in 24 % yield (Table 1, entry 1). Other palladium precursors, such as [Pd2(dba)3], Pd(OAc)2, and PdCl2 were also tested, yet the yields remained very low (Table 1, entries 2–4). After screening different palladium precursors, bases, and solvents (for details, see the Supporting Information, Table S1), we found that by using 2 mol % Pd/C (10 wt %) as the catalyst and NaHCO3 as the base in methyl tert-butyl ether, the yield of 3 a could be improved to 48 % (Table 1, entries 5–8). Further increases in the catalyst loading (4 mol %) and amounts of 2 a (3 equiv) and base (3 equiv) led to a 66 % yield of 3 a (Table 1, entry 9). Other bases, such as Na2CO3, NaOAc, Cs2CO3, K3PO4, and DABCO, were all much inferior for this reaction (Table S1). During exploration of the ligand effects for this reaction, we discovered that the yields of 3 a was almost unaffected by different types of ligands (see the Supporting Information, Table S1, entries 23–25). Accordingly, we carried out a control reaction with 2 mol % Pd/C under ligand-free conditions; to our surprise, 69 % yield of 3 a was obtained (Table 1, entry 12). However, decreasing the catalyst loading to 1 mol % caused a significant decrease in the yield (26 %). To aid the practicality of this reaction, we attempted to use N-chloropiperidine that was generated in situ by chlorinating reagents (Table 2). Under similar conditions to those for Table 1, entry 12, we were glad to find that 66 % yield of 3 a was obtained by using two equivalents of piperidine and 2.1 equivalents of N-chlorosuccinimide (NCS) at 40 8C (Table 2, entry 1). Lesser amounts of piperidine, reduced catalyst loadings, or lower temperatures all diminished the yield of 3 a to various extents (Table 2, entries 1 and 2). Control experiments confirmed that both the base and Pd/C were indispensable for the carbonylation reaction, as no product was detected when either of them was omitted (Table 2, entry 3). Variations in the &
x [equiv]
[a] Reaction conditions: 1 a (0.25 mmol), piperidine (0.5 mmol), NCS (0.525 mmol), 10 wt % Pd/C (5.32 mg, 5 mmol), tBuOMe (2 mL), 16 h. [b] GC yield determined by using hexadecane as the internal standard. [c] 1 mol % Pd/C was used. [d] Either Pd/C or NaHCO3 was omitted. [e] Yield of isolated product. [f] 0.8 equivalents of TCCA (trichloroisocyanuric acid) was used in place of NCS. [g] NBS (N-bromosuccinimide) was used in place of NCS.
[a] Conditions (unless otherwise stated): 1 a (0.25 mmol), 2 a [0.5 mmol (entries 1–8) or 0.75 mmol (entries 9–12)], 40 8C, CO (50 bar), 16 h. [b] GC yields were determined by using hexadecane as the internal standard. [c] T = 50 8C, 40 bar CO. [d] No ligand was added. [e] 1 mol % Pd/C was used. DME = 1,2-dimethoxyethane; MTBE = methyl tert-butyl ether.
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Entry [b]
Scheme 3. Cross-coupling between 1 a and 2 a under CO-free conditions.
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Scheme 4. Ruling out carbamoyl chloride as responsible intermediate for the amide formation.
ditions (Scheme 4 b).[11] Therefore, 5 a should not be the intermediate responsible for the formation of 3 a. The above observations cast some doubts on the proposed reaction pathway (Scheme 2). Given that high pressures are usually employed in radical carbonylations[12] and that Nchloroamines tend to undergo single electron transfer (SET) to lower oxidation-state metals, such as FeII and CuI, to generate amino radicals,[13, 5a] we envisioned that the reaction might involve a radical process. When 40 mol % TEMPO (2,2,6,6-tetramethylpiperidin-1-oxyl) was added as a free-radical scavenger, the reaction was totally impeded (Scheme 5 a). Moreover, the formation of piperidine-1-carbonyl chloride (5 a) from N-chloropiperidine (2 a) was also totally inhibited by addition of one equivalent of TEMPO to the reaction (Scheme 5 b).[14]
Scheme 6. Proposed hybrid organometallic–radical catalytic cycle of the electrophilic aminocarbonylation.
reductive elimination of intermediate B; 3) no formation of noncarbonylative cross-coupling product R NR1R2 (Scheme 3). We also endeavored to trap the possible dialkylaminyl or carbamoyl radical A intermediates with TEMPO through various methods (see the Supporting Information), but failed to obtain any convincing trapping products. Further support for the proposed hybrid organometallic– radical mechanism came from the the scope for variation of the metal catalyst.[15] For example, some complexes of Cu, Fe, Ni and Ru also led to the product in various yields (see the Supporting Information, Table S3). To demonstrate the usefulness of this procedure for the synthesis of amides, we extended the substrate scope to various amines and boronic acids (Table 3). Either electron-withdrawing or -donating groups on the phenyl ring of the arylboronic acids were tolerated and moderate to good yields of the desired products were obtained. Ortho-substituted arylboronic acids also led to the corresponding amides in moderate yields (3 i and 3 k). Unfortunately, heteroarylboronic acids underwent decomposition under these conditions and the yields were rather low (3 l–n). In contrast, styrylboronic acid could be converted to cinnamamide (3 o) in 50 % yield. Pleasingly, alkylboronic acids were also feasible substrates for the aminocarbonylation. For example, N-valeryl (3 p) and N-cyclohexanoyl (3 q) piperidine were obtained in 93 % and 76 % yields respectively. Moreover, various amines, such as morpholine, N,N-dihexylamine, diethylamine, pyrrolidine, and azepane, were also all amenable to the reaction. However, bulkier amines such as diisopropylamine led to much lower yields (3 w). When 2,2,6,6tetramethylpiperidine was used as the amine, no desired amide was isolated and the intermediate N-chlorinated amine was detected instead by GC-MS. Bromoaryl substituents could be tolerated on either coupling partner under these mild reaction conditions (3 t–x). The resultant bromo-containing amides could then be further elaborated by palladium-catalyzed coupling reactions. Primary amines, such as aniline, wer also inves-
Scheme 5. Free-radical trapping experiment with TEMPO.
Based on all of these results, we proposed a radical process for the aminocarbonylation (Scheme 6). Firstly, dialkylaminyl radical (R1R2N·) is generated by SET from the N-chloro dialkylamine (R1R2NCl) to the metal (Mn + ; e.g., Pd0), and the oxidation state of metal is increased by + 1. At higher pressure, CO is trapped by the dialkylaminyl radicals to form carbamoyl radical A. Next, SET from A to the oxidized metal (Mn + 1Cl) produces the carbamoyl–metal intermediate B, which undergoes transmetallation with boronic acid to form the product-releasing intermediate C. This radical mechanism is consistent with the following observations: 1) Formation of the byproduct via recombination of the dialkylaminyl radical and the carbamoyl radical A; 2) formation of the carbamoyl chloride resulting from the Chem. Eur. J. 2015, 21, 1 – 6
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Communication Experimental Section
Table 3. Substrate scope of the electrophilic aminocarbonylation.[a]
General procedure of electrophilic aminocarbonylation reactions: To each Wheaton vial (10 mL volume) equipped with a septum, a small cannula, and a stirring bar was added 10 wt % Pd/C (21.3 mg, 20 mmol), boronic acid (1 mmol), NCS (280 mg, 2.1 mmol), and NaHCO3 (252 mg, 3 mmol). The vials were then purged with argon before tBuOMe (5 mL) was added to the reaction mixture by syringe. Piperidine (120 mL, 2 mmol) was then added to each vial through a Hamilton syringe. The vials were then placed on an alloy plate and transferred into a 300 mL autoclave of the 4560 series from Parr Instruments under air. After flushing the autoclave three times with CO, a pressure of 50 to 80 bar was set and the reaction was performed for 18 h at 45 8C. Afterwards, the autoclave was cooled to room temperature and the pressure was released carefully. The solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel (eluent: pentane/ethyl acetate). For the specific screened conditions, see the Supporting Information.
Acknowledgements The authors thank the State of Mecklenburg-Vorpommern, the Bundesministerium fr Bildung und Forschung (BMBF), and the Deutsche Forschungsgemeinschaft for financial support. We also appreciate the general support from Prof. Matthias Beller of LIKAT and the helpful discussions with Chaoren Shen of LIKAT. Keywords: amides · aminocarbonylation · boronic acids · Nchloroamine · palladium
[1] A. Schoenberg, R. F. Heck, J. Org. Chem. 1974, 39, 3327. [2] a) R. Skoda-Foldes, L. Kollr, Curr. Org. Chem. 2002, 6, 1097; b) C. F. J. Barnard, Organometallics 2008, 27, 5402; c) A. Brennfhrer, H. Neumann, M. Beller, Angew. Chem. Int. Ed. 2009, 48, 4114; Angew. Chem. 2009, 121, 4176; d) W. Fang, Q. Deng, M. Xu, T. Tu, Org. Lett. 2013, 15, 3678; e) J. S. Quesnel, B. A. Arndtsen, J. Am. Chem. Soc. 2013, 135, 16841; f) P. Xie, C. Xia, H. Huang, Org. Lett. 2013, 15, 3370; g) S. D. Friis, T. Skrydstrup, S. L. Buchwald, Org. Lett. 2014, 16, 4296; h) T. Xu, H. Alper, J. Am. Chem. Soc. 2014, 136, 16970. [3] a) F. Ozawa, T. Sugimoto, Y. Yuasa, M. Santra, T. Yamamoto, A. Yamamoto, Organometallics 1984, 3, 683; b) L. Huang, F. Ozawa, A. Yamamoto, Organometallics 1990, 9, 2603. [4] a) C. He, C. Chen, J. Cheng, C. Liu, W. Liu, Q. Li, A. Lei, Angew. Chem. Int. Ed. 2008, 47, 6414; Angew. Chem. 2008, 120, 6514; b) T. J. Barker, E. R. Jarvo, J. Am. Chem. Soc. 2009, 131, 15598; c) T. Kawano, K. Hirano, T. Satoh, M. Miura, J. Am. Chem. Soc. 2010, 132, 6900; d) T. Daskapan, ARKIVOC (Gainesville, FL, U.S.) 2011, 230; e) R. P. Rucker, A. M. Whittaker, H. Dang, G. Lalic, Angew. Chem. Int. Ed. 2012, 51, 3953; Angew. Chem. 2012, 124, 4019; f) Q. Xiao, L. Tian, R. Tan, Y. Xia, D. Qiu, Y. Zhang, J. Wang, Org. Lett. 2012, 14, 4230; g) X. Yan, C. Chen, Y. Zhou, C. Xi, Org. Lett. 2012, 14, 4750; h) G. Lalic, R. P. Rucker, Synlett 2012, 24, 269; i) M. H. Nguyen, A. B. Smith, III, Org. Lett. 2013, 15, 4872; j) X. Qian, Z. Yu, A. Auffrant, C. Gosmini, Chem. Eur. J. 2013, 19, 6225; k) S. L. McDonald, C. E. Hendrick, Q. Wang, Angew. Chem. Int. Ed. 2014, 53, 4667; Angew. Chem. 2014, 126, 4755. [5] a) P. Kovacic, M. K. Lowery, K. W. Field, Chem. Rev. 1970, 70, 639; b) E. Erdik, M. Ay, Chem. Rev. 1989, 89, 1947. [6] a) H. Tsutsui, K. Narasaka, Chem. Lett. 1999, 28, 45; b) H. Tsutsui, M. Kitamura, K. Narasaka, Bull. Chem. Soc. Jpn. 2002, 75, 1451; c) M. Kitamura, D. Kudo, K. Narasaka, ARKIVOC (Gainesville, FL, U.S.) 2006, 148; d) Y. Tan,
[a] Reaction conditions: RB(OH)2 (1 mmol), 10 wt % Pd/C (21 mg, 0.02 mmol), NCS (280 mg, 2.1 mmol), NaHCO3 (252 mg, 3 mmol), tBuOMe (5 mL), 45 8C, CO (80 bar).
tigated, but no desired amide was formed, which might be attributed to the decreased stability of the N-chloroamine intermediate. In summary, we have realized the first transition metal-catalyzed umpolung aminocarbonylation reaction of N-chloroamines and boronic acids. Using Pd/C as a ligand-free and recyclable catalyst (see the Supporting Information), a series of aliphatic and aromatic amides were synthesized under mild conditions. Due to the near-ambient temperature, aryl bromides and iodides could also be tolerated under the reaction conditions. Besides palladium, copper, iron, ruthenium and nickel catalysts also led to the carbonylation products. Additionally, the N-chloroamines applied herein could be generated in situ, which is a major advantage in organic synthesis. Preliminary experiments and analysis indicated a hybrid organometallic– radical mechanism for this transformation. Further investigation into the mechanism and other carbonylation reactions involving N Cl bonds are currently underway in our group. &
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[7] [8] [9] [10]
[11] [12]
Acc. Chem. Res. 2014, 47, 1563; c) C. Chatgilialoglu, D. Crich, M. Komatsu, I. Ryu, Chem. Rev. 1999, 99, 1991. [13] a) F. Minisci, R. Galli, Tetrahedron Lett. 1964, 5, 167; b) F. Minisci, R. Galli, Tetrahedron Lett. 1966, 7, 2531. [14] a) T. Saegusa, T. Tsuda, Y. Isegawa, J. Org. Chem. 1971, 36, 858; b) C. Davies, M. Kilner, J. Catal. 1992, 136, 403. [15] U. Jahn in Topics in Current Chemistry, Vol. 320: Radicals in Synthesis III (Eds.: M. Heinrich, A. Gansuer), Springer, Heidelberg, 2012, pp.121 – 452.
J. F. Hartwig, J. Am. Chem. Soc. 2010, 132, 3676; e) N. J. Race, J. F. Bower, Org. Lett. 2013, 15, 4616. J. Helaja, R. Gottlich, Chem. Commun. 2002, 720. a) H. E. Bryndza, W. Tam, Chem. Rev. 1988, 88, 1163; b) M. D. Fryzuk, C. D. Montgomery, Coord. Chem. Rev. 1989, 95, 1. Y.-L. Zhong, P. G. Bulger, Org. Synth. 2010, 87, 8. a) Q. Liu, H. Zhang, A. Lei, Angew. Chem. Int. Ed. 2011, 50, 10788; Angew. Chem. 2011, 123, 10978; b) X.-F. Wu, H. Neumann, M. Beller, ChemSusChem 2013, 6, 229. Y.-Z. Duan, M.-Z. Deng, Synlett 2005, 355. a) I. Ryu, N. Sonoda, Angew. Chem. Int. Ed. Engl. 1996, 35, 1050; Angew. Chem. 1996, 108, 1140; b) S. Sumino, A. Fusano, T. Fukuyama, I. Ryu,
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COMMUNICATION & Aminocarbonylation W. Li, X.-F. Wu* && – && Palladium-Catalyzed Aminocarbonylation of NChloroamines with Boronic Acids
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Umpolung aminocarbonylation: The first palladium-catalyzed carbonylative cross-coupling between N-chloroamines and organoboronic acids has been realized. Various amides were isolated in moderate to excellent yields from reactions under mild temperatures with
ligand-free Pd/C as the catalyst. Not only arylboronic acids, but also alkenyland alkylboronic acids are applied as the substrates and bromide and iodide substituents in the substrates are well tolerated.
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& Aminocarbonylation
Palladium-Catalyzed Aminocarbonylation of N-Chloroamines with Boronic Acids Wanfang Li and Xiao-Feng Wu*[a] dition to the C X bond carbonylation reactions, the investigation of carbonylative transformation of N X bonds is of interest to both academic and industrial researchers. However, this transformation (Scheme 1 b) remains unknown in the literature. The use of N X-based substrates in metal-catalyzed cross-coupling reactions has recently been described.[4] Compared with C X-based coupling reactions, these transformations proceeded under milder conditions and tolerated a wider array of functional groups, due to the high and varied reactivity of N X bonds.[5] In light of all of these developments, we became interested in developing an N X bond-based carbonylation reaction. Based on the widely accepted mechanism of palladium-catalyzed carbonylative cross-coupling between aryl halides and amines,[3] we envisioned that an electrophilic aminocarbonylation reaction is conceptually viable (Scheme 2). Firstly, the oxi-
Abstract: Aryl (pseudo)halide-based (C X) carbonylation reactions have been extensively studied during the past few decades. From both academic and synthetic points of view, the carbonylative transformation of N X bonds represents an interesting and attractive area of investigation. In light of this, the first carbonylative cross-coupling between N-chloroamines and organoboronic acids has been developed. This new type of aminocarbonylation proceeds at mild temperatures (45–55 8C) with 2 mol % Pd/C (10 wt %) as the ligand-free catalyst. Not only arylboronic acids, but also alkenyl- and alkylboronic acids can be applied as the substrates and bromide and iodide substituents in the substrates are well tolerated. Initial mechanistic investigations have also been performed.
Palladium-catalyzed aminocarbonylation of aromatic and alkenic (pseudo)halides (C X bonds), which was first reported by Schoenberg and Heck in 1974,[1] has since evolved into a powerful and reliable tool for amide bond formation (Scheme 1 a).[2] Typically, these reactions are initialized by the oxidative addition of C(sp2) X bonds onto Pd0 precatalysts. The ensuing CO insertion, nucleophilic attack, and reductive elimination steps contribute to the whole catalytic cycle.[3] In all of these traditional aminocarbonylation reactions, C(sp2) X species have acted as the electrophile and amines as the nucleophile. In ad-
Scheme 2. Proposed catalytic cycle of electrophilic aminocarbonylation.
dative addition of N O[6] and N Cl[7] bonds to Pd0 species has been proposed in hetero-Heck reactions with some preliminary evidence. In view of the unprecedented, possibly quite difficult, CO insertion into palladium–amide bonds,[8] that is, the formation of intermediate C’ (Scheme 2), we presumed that transmetallation proceeded before CO insertion, whereby the acyl PdII intermediate C, rather than the aryl carbamoyl PdII intermediate D’, would form.[3b] In the final reductive elimination step, the product was released and Pd0 was regenerated. To implement the above ideas, we embarked on our experiments with phenylboronic acid (1 a) and N-chloropiperidine (2 a), which could be easily prepared by chlorination of piperidine with aqueous sodium hypochlorite.[9] Initially, we carried out the reaction with 3 mol % [Pd(PPh3)4], two equivalents of 2 a, and K2CO3 as the base in THF, which afforded benzoyl pi-
Scheme 1. Carbonylation procedures: a) C X bond-based carbonylation; b) N X bond-based carbonylation.
[a] Dr. W. Li, Prof. Dr. X.-F. Wu Leibniz-Institut fr Katalyse e.V. an der Universitt Rostock Albert-Einstein-Strasse 29 a, 18059 Rostock (Germany) E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201500779. Chem. Eur. J. 2015, 21, 1 – 6
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Communication Table 1. Selected optimization of the carbonylative cross-coupling between 1 a and 2 a.[a]
Table 2. Selected optimization of the reaction conditions using in situgenerated N-chloropiperidine.[a]
Entry
Pd (mol %)
Base (equiv)
Solvent
Yield [%]
1[c] 2[c] 3[c] 4[c] 5 6 7 8 9 10 11 12[d]
[Pd(PPh3)4] (3) [Pd2(dba)3] (3) Pd(OAc)2 (3) PdCl2 (3) Pd/C (2) Pd/C (2) Pd/C (2) Pd/C (2) Pd/C (4) Pd/C (4) Pd/C (4) Pd/C (2)
K2CO3 (2) K2CO3 (2) K2CO3 (2) K2CO3 (2) NaHCO3 (2) NaHCO3 (2) NaHCO3 (3) NaHCO3 (3) NaHCO3 (3) Na2CO3(3) NaOAc (3) NaHCO3 (3)
THF THF THF THF dioxane toluene DME MTBE MTBE MTBE MTBE MTBE
24 21 13 29 33 27 21 48 66 32 41 69 (26[e])
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y [bar]
T [8C]
Yield [%][b]
1 2 3 4 5 6 7 8
2 2 2 3 3 3 3 3
50 40 50 50 50 80 50 50
40 35 45 45 60 45 45 45
66 (46[c]) 33 67 (0[d]) 73 (70[e]) 71 81 41[f] 0[g]
base amount, reaction temperature and CO pressure led to a much higher yield of 3 a, if CO pressure is 80 bar (81 %, Table 2, entry 6). Much like the reactions with with preformed N-chloropiperidine, other homogeneous palladium precursors, such as [Pd(PPh3)4], Pd(dba)2 and Pd(OAc)2, were again much less effective for this reaction (see the Supporting Information, Table S2). Other N-halogenation reagents, TCCA (trichloroisocyanuric acid) and NBS (N-bromosuccinimide), were much less reactive than NCS (Table 2, entry 7 and 8). Importantly, no formation of 3 a was detected when NCS was replaced with oxidants such as BQ (benzoquinone), DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone), K2S2O4, tBuOOtBu, or tBuOOH (see the Supporting Information, Table S3). These results can rule out the occurrence of the usual oxidative carbonylation process.[10] To gain further mechanistic insight into the reaction, several control experiments were carried out. In all of the above optimization reactions, and even in the absence of CO gas, we detected no N-phenylpiperidine (4 a, Scheme 3), which would likely be produced from the reductive elimination of intermediate B in Scheme 2.[4a] During the optimization process, we also observed that carbamoyl chloride (5 a) and urea were produced as byproducts in some cases. Specifically, piperidine-1-carbonyl chloride 5 a was obtained in 87 % GC yield when no base was added (Scheme 4 a). Nevertheless, carbamoyl chloride did not undergo cross-coupling with phenylboronic acid (1 a) under our con-
peridine 3 a in 24 % yield (Table 1, entry 1). Other palladium precursors, such as [Pd2(dba)3], Pd(OAc)2, and PdCl2 were also tested, yet the yields remained very low (Table 1, entries 2–4). After screening different palladium precursors, bases, and solvents (for details, see the Supporting Information, Table S1), we found that by using 2 mol % Pd/C (10 wt %) as the catalyst and NaHCO3 as the base in methyl tert-butyl ether, the yield of 3 a could be improved to 48 % (Table 1, entries 5–8). Further increases in the catalyst loading (4 mol %) and amounts of 2 a (3 equiv) and base (3 equiv) led to a 66 % yield of 3 a (Table 1, entry 9). Other bases, such as Na2CO3, NaOAc, Cs2CO3, K3PO4, and DABCO, were all much inferior for this reaction (Table S1). During exploration of the ligand effects for this reaction, we discovered that the yields of 3 a was almost unaffected by different types of ligands (see the Supporting Information, Table S1, entries 23–25). Accordingly, we carried out a control reaction with 2 mol % Pd/C under ligand-free conditions; to our surprise, 69 % yield of 3 a was obtained (Table 1, entry 12). However, decreasing the catalyst loading to 1 mol % caused a significant decrease in the yield (26 %). To aid the practicality of this reaction, we attempted to use N-chloropiperidine that was generated in situ by chlorinating reagents (Table 2). Under similar conditions to those for Table 1, entry 12, we were glad to find that 66 % yield of 3 a was obtained by using two equivalents of piperidine and 2.1 equivalents of N-chlorosuccinimide (NCS) at 40 8C (Table 2, entry 1). Lesser amounts of piperidine, reduced catalyst loadings, or lower temperatures all diminished the yield of 3 a to various extents (Table 2, entries 1 and 2). Control experiments confirmed that both the base and Pd/C were indispensable for the carbonylation reaction, as no product was detected when either of them was omitted (Table 2, entry 3). Variations in the &
x [equiv]
[a] Reaction conditions: 1 a (0.25 mmol), piperidine (0.5 mmol), NCS (0.525 mmol), 10 wt % Pd/C (5.32 mg, 5 mmol), tBuOMe (2 mL), 16 h. [b] GC yield determined by using hexadecane as the internal standard. [c] 1 mol % Pd/C was used. [d] Either Pd/C or NaHCO3 was omitted. [e] Yield of isolated product. [f] 0.8 equivalents of TCCA (trichloroisocyanuric acid) was used in place of NCS. [g] NBS (N-bromosuccinimide) was used in place of NCS.
[a] Conditions (unless otherwise stated): 1 a (0.25 mmol), 2 a [0.5 mmol (entries 1–8) or 0.75 mmol (entries 9–12)], 40 8C, CO (50 bar), 16 h. [b] GC yields were determined by using hexadecane as the internal standard. [c] T = 50 8C, 40 bar CO. [d] No ligand was added. [e] 1 mol % Pd/C was used. DME = 1,2-dimethoxyethane; MTBE = methyl tert-butyl ether.
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Scheme 3. Cross-coupling between 1 a and 2 a under CO-free conditions.
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Scheme 4. Ruling out carbamoyl chloride as responsible intermediate for the amide formation.
ditions (Scheme 4 b).[11] Therefore, 5 a should not be the intermediate responsible for the formation of 3 a. The above observations cast some doubts on the proposed reaction pathway (Scheme 2). Given that high pressures are usually employed in radical carbonylations[12] and that Nchloroamines tend to undergo single electron transfer (SET) to lower oxidation-state metals, such as FeII and CuI, to generate amino radicals,[13, 5a] we envisioned that the reaction might involve a radical process. When 40 mol % TEMPO (2,2,6,6-tetramethylpiperidin-1-oxyl) was added as a free-radical scavenger, the reaction was totally impeded (Scheme 5 a). Moreover, the formation of piperidine-1-carbonyl chloride (5 a) from N-chloropiperidine (2 a) was also totally inhibited by addition of one equivalent of TEMPO to the reaction (Scheme 5 b).[14]
Scheme 6. Proposed hybrid organometallic–radical catalytic cycle of the electrophilic aminocarbonylation.
reductive elimination of intermediate B; 3) no formation of noncarbonylative cross-coupling product R NR1R2 (Scheme 3). We also endeavored to trap the possible dialkylaminyl or carbamoyl radical A intermediates with TEMPO through various methods (see the Supporting Information), but failed to obtain any convincing trapping products. Further support for the proposed hybrid organometallic– radical mechanism came from the the scope for variation of the metal catalyst.[15] For example, some complexes of Cu, Fe, Ni and Ru also led to the product in various yields (see the Supporting Information, Table S3). To demonstrate the usefulness of this procedure for the synthesis of amides, we extended the substrate scope to various amines and boronic acids (Table 3). Either electron-withdrawing or -donating groups on the phenyl ring of the arylboronic acids were tolerated and moderate to good yields of the desired products were obtained. Ortho-substituted arylboronic acids also led to the corresponding amides in moderate yields (3 i and 3 k). Unfortunately, heteroarylboronic acids underwent decomposition under these conditions and the yields were rather low (3 l–n). In contrast, styrylboronic acid could be converted to cinnamamide (3 o) in 50 % yield. Pleasingly, alkylboronic acids were also feasible substrates for the aminocarbonylation. For example, N-valeryl (3 p) and N-cyclohexanoyl (3 q) piperidine were obtained in 93 % and 76 % yields respectively. Moreover, various amines, such as morpholine, N,N-dihexylamine, diethylamine, pyrrolidine, and azepane, were also all amenable to the reaction. However, bulkier amines such as diisopropylamine led to much lower yields (3 w). When 2,2,6,6tetramethylpiperidine was used as the amine, no desired amide was isolated and the intermediate N-chlorinated amine was detected instead by GC-MS. Bromoaryl substituents could be tolerated on either coupling partner under these mild reaction conditions (3 t–x). The resultant bromo-containing amides could then be further elaborated by palladium-catalyzed coupling reactions. Primary amines, such as aniline, wer also inves-
Scheme 5. Free-radical trapping experiment with TEMPO.
Based on all of these results, we proposed a radical process for the aminocarbonylation (Scheme 6). Firstly, dialkylaminyl radical (R1R2N·) is generated by SET from the N-chloro dialkylamine (R1R2NCl) to the metal (Mn + ; e.g., Pd0), and the oxidation state of metal is increased by + 1. At higher pressure, CO is trapped by the dialkylaminyl radicals to form carbamoyl radical A. Next, SET from A to the oxidized metal (Mn + 1Cl) produces the carbamoyl–metal intermediate B, which undergoes transmetallation with boronic acid to form the product-releasing intermediate C. This radical mechanism is consistent with the following observations: 1) Formation of the byproduct via recombination of the dialkylaminyl radical and the carbamoyl radical A; 2) formation of the carbamoyl chloride resulting from the Chem. Eur. J. 2015, 21, 1 – 6
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Table 3. Substrate scope of the electrophilic aminocarbonylation.[a]
General procedure of electrophilic aminocarbonylation reactions: To each Wheaton vial (10 mL volume) equipped with a septum, a small cannula, and a stirring bar was added 10 wt % Pd/C (21.3 mg, 20 mmol), boronic acid (1 mmol), NCS (280 mg, 2.1 mmol), and NaHCO3 (252 mg, 3 mmol). The vials were then purged with argon before tBuOMe (5 mL) was added to the reaction mixture by syringe. Piperidine (120 mL, 2 mmol) was then added to each vial through a Hamilton syringe. The vials were then placed on an alloy plate and transferred into a 300 mL autoclave of the 4560 series from Parr Instruments under air. After flushing the autoclave three times with CO, a pressure of 50 to 80 bar was set and the reaction was performed for 18 h at 45 8C. Afterwards, the autoclave was cooled to room temperature and the pressure was released carefully. The solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel (eluent: pentane/ethyl acetate). For the specific screened conditions, see the Supporting Information.
Acknowledgements The authors thank the State of Mecklenburg-Vorpommern, the Bundesministerium fr Bildung und Forschung (BMBF), and the Deutsche Forschungsgemeinschaft for financial support. We also appreciate the general support from Prof. Matthias Beller of LIKAT and the helpful discussions with Chaoren Shen of LIKAT. Keywords: amides · aminocarbonylation · boronic acids · Nchloroamine · palladium
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[a] Reaction conditions: RB(OH)2 (1 mmol), 10 wt % Pd/C (21 mg, 0.02 mmol), NCS (280 mg, 2.1 mmol), NaHCO3 (252 mg, 3 mmol), tBuOMe (5 mL), 45 8C, CO (80 bar).
tigated, but no desired amide was formed, which might be attributed to the decreased stability of the N-chloroamine intermediate. In summary, we have realized the first transition metal-catalyzed umpolung aminocarbonylation reaction of N-chloroamines and boronic acids. Using Pd/C as a ligand-free and recyclable catalyst (see the Supporting Information), a series of aliphatic and aromatic amides were synthesized under mild conditions. Due to the near-ambient temperature, aryl bromides and iodides could also be tolerated under the reaction conditions. Besides palladium, copper, iron, ruthenium and nickel catalysts also led to the carbonylation products. Additionally, the N-chloroamines applied herein could be generated in situ, which is a major advantage in organic synthesis. Preliminary experiments and analysis indicated a hybrid organometallic– radical mechanism for this transformation. Further investigation into the mechanism and other carbonylation reactions involving N Cl bonds are currently underway in our group. &
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Chem. Eur. J. 2015, 21, 1 – 6
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COMMUNICATION & Aminocarbonylation W. Li, X.-F. Wu* && – && Palladium-Catalyzed Aminocarbonylation of NChloroamines with Boronic Acids
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Umpolung aminocarbonylation: The first palladium-catalyzed carbonylative cross-coupling between N-chloroamines and organoboronic acids has been realized. Various amides were isolated in moderate to excellent yields from reactions under mild temperatures with
ligand-free Pd/C as the catalyst. Not only arylboronic acids, but also alkenyland alkylboronic acids are applied as the substrates and bromide and iodide substituents in the substrates are well tolerated.
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