Published on 28 July 2014. Downloaded by New Mexico State University on 09/09/2014 09:22:39.
Cite this: Chem. Commun., 2014, 50, 10409
View Article Online View Journal | View Issue
Metal-templated enantioselective enamine/ H-bonding dual activation catalysis† Haohua Huo,a Chen Fu,a Chuanyong Wang,a Klaus Harmsa and Eric Meggers*ab
Received 18th June 2014, Accepted 21st July 2014 DOI: 10.1039/c4cc04636f www.rsc.org/chemcomm
An octahedral bis-cyclometalated iridium(III) complex catalyzes the enantioselective a-amination of aldehydes with catalyst loadings down to 0.1 mol%. In this metal-templated design, the metal serves as a structural center and provides the exclusive source of chirality, whereas the catalysis is mediated through the organic ligand sphere.
Dual activation by multifunctional catalysts has emerged as a powerful concept for the design of high performance asymmetric metal-based catalysts and asymmetric organocatalysts.1 A typical bifunctional catalyst individually interacts with both the nucleophile and electrophile (dual activation) through at least overall two functional groups (bi- or multifunctional catalysis). However, although appealing as a concept, the design of high performance multifunctional catalysts remains challenging since it relies on a distinct positioning of carefully chosen functional groups within the chiral catalyst template in order to gain a maximum advantage from functional group cooperativity. Hence, one can assume that most multifunctional, dual activation catalysts do not reach the theoretically possible rate acceleration and asymmetric induction. Recently, we reported octahedral chiral-at-metal iridium(III) complexes as low-loading asymmetric catalysts which mainly rely on three defined hydrogen bonds between substituents on the periphery of the metal complexes and the substrates, and in which the iridium center serves as an unreactive bystander fulfilling a purely structural role.2–4 We hypothesize that inert octahedral metal complexes are general, powerful templates for the efficient design of multifunctional catalysts since octahedral stereocenters allow the straightforward construction of molecular entities with high shape and stereochemical complexity. Furthermore, steric crowding around the metal stereocenter combined with chelate effects often
result in a limited conformational flexibility which is not only advantageous for entropic reasons but also simplifies an intuitive and rational catalyst optimization. Herein, we now wish to demonstrate how a chiral-at-metal octahedral iridium(III) complex can serve as a scaffold for the straightforward rational design of a low loading asymmetric enamine/H-bonding dual activation catalyst (Fig. 1).5 We started our study by designing the substitutionally and configurationally inert bis-cyclometalated octahedral iridium(III) complex L-Ir1 as our first generation bifunctional enamine catalyst.1e,6 In L-Ir1, a coordinated 2-pyridyl-5,6-dihydro-4H-pyrrolo[3,4-d][1,3]oxazole ligand7 contains a secondary amine for performing enamine catalysis, while a hydroxyl substituent at the 5-position of the benzoxazole ligands is supposed to serve as a hydrogen bonding donor for the activation and positioning of an electrophile. As a model reaction we chose the direct catalytic a-amination of aldehydes with azodicarboxylates as the nitrogen source, since it represents one of the simplest methods for the construction of a nitrogen-connected stereogenic carbon and provides a convenient access to many classes
¨t Marburg, Hans-Meerwein-Straße, Fachbereich Chemie, Philipps-Universita 35043 Marburg, Germany. E-mail: [email protected] b College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, People’s Republic of China † Electronic supplementary information (ESI) available: Experimental details and analytical data, including chiral HPLC traces and X-ray crystallographic data. CCDC 1006275. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4cc04636f
Reaction conditions: to a mixture of 2a (0.20 mmol) and iridium catalyst L-Ir1–5 (0.1–4 mol%) in anhydrous toluene (2.0 mL for entries 1–5 and 9, 0.2 mL for entries 6–8), DMF (0.2 mL) or MeOH (0.2 mL) at 0 1C was added the aldehyde 1a (0.30 mmol). After being stirred at 0 1C or room temperature for 1.5–36 h under reduced light, MeOH (2.0 mL) was added, followed by the careful addition of NaBH4 (0.26 mmol) at 0 1C. The products were isolated after basic workup and chromatography. b Isolated yields. c Enantiomeric excess determined by chiral HPLC analysis.
of nitrogen-containing optically active scaﬀolds.8,9 Accordingly, when we reacted aldehyde 1a with dibenzyl azodicarboxylate (2a) in toluene at 0 1C in the presence of 4 mol% of L-Ir1, we obtained the configurationally stable N-(benzyloxycarbonylamino)oxazolidinone (S)-3a after in situ reduction with NaBH4 and NaOH-induced cyclization in a yield of 87% with modest but encouraging 31% ee (Table 1, entry 1).10 A repositioning of the hydrogen-bond donor by replacing the phenolic OH by a hydroxymethyl group slightly improved the ee value to 39% (L-Ir2; Table 1, entry 2). We next speculated that the low enantiodiﬀerentiation might be the result of a missing discrimination between the two possible enamine conformations upon reaction of the secondary amine of L-Ir2 with aldehyde 1a, so that the introduction of steric hindrance at the 5-position of the metalated phenyl group would provide the necessary bias towards a single enamine conformation. Indeed, L-Ir3, containing a 2,6-Me2Ph substituent at the 5-position of the metalated phenyl group provided oxazolidinone (S)-3a with a significantly improved ee value of 65% (Table 1, entry 3). Increasing this steric hindrance with the more bulky 2,4,6-iPr3Ph substituent (L-Ir4) further improved the enantioselectivity to 97% ee at a yield of 96% with 4 mol% of L-Ir4 (Table 1, entry 4). Even with a reduced catalyst loading of 1 mol% L-Ir4, the oxazolidinone (S)-3a was obtained with 91% ee at room temperature (Table 1, entry 5). Finally, upon optimization of the reaction conditions by increasing the concentrations of aldehyde 1a (1.5 M) and azodicarboxylate 2a (1.0 M), the reaction time was significantly decreased while improving the enantiodiﬀerentiation to 97% ee with 1 mol% L-Ir4 (entry 6). To our delight, under these conditions, the catalyst loading could be decreased further down to 0.2 (entry 7) and even 0.1 mol% (entry 8) while retaining satisfactory enantioselectivities of 94% and 91% ee, respectively.‡
10410 | Chem. Commun., 2014, 50, 10409--10411
Table 2 Substrate scope of the enantioselective a-amination of aldehydes with iridium catalyst L-Ir4a
Reaction conditions: to a mixture of azodicarboxylate 2a–c (0.2 mmol) and L-Ir4 (1.0 mol%) in anhydrous toluene (0.2 mL, 1.0 M) at 0 1C was added the aldehyde 1a–j (0.30 mmol, 1.5 M). After being stirred at RT for 12–15 h, MeOH (0.2 mL) was added followed by the careful addition of NaBH4 (10 mg, 0.26 mmol) at 0 1C. The products were isolated after basic workup (except for entries 11 and 12) and chromatography. b Isolated yields. c Enantiomeric excess determined by chiral HPLC analysis. d No suitable chiral HPLC conditions to resolve the two enantiomers were found for the corresponding cyclization products.
Under the assumption that the minor enantiomer is formed from the uncatalyzed background reaction, for 0.1 mol% catalyst loading one can calculate an impressive turnover number of almost 103 with a rate acceleration of 1.0 104. Table 2 reveals the substrate scope of L-Ir4, providing the corresponding b-hydroxyhydrazines (after in situ reduction of the aldehyde) or oxazolidinones (after NaOH-induced cyclization of the b-hydroxyhydrazines) with satisfactory yields and high enantioselectivities. Thus, rational design with just a few rounds of optimization aﬀorded the highly active chiral-only-atmetal iridium catalyst L-Ir4 for the enantioselective a-amination of aldehydes. The mode of action of iridium complex L-Ir4 can be rationalized by a bifunctional, dual activation catalysis which converts the aldehyde into a nucleophilic enamine, while at the same time activating the azodicarboxylate electrophile through hydrogen bonding with one OH-group (Fig. 2). The asymmetric induction is then achieved by sterically enforcing the (E)-syn enamine conformation through sterically preventing the unfavored
Fig. 2 Proposed enamine/H-bonding mechanism of the a-amination of aldehydes (blue) with azodicarboxylates (green) catalyzed by iridium complex L-Ir4.
of functional groups in the three-dimensional space, whereas the limited flexibility of the metal scaﬀold provides entropic benefits and promotes the rational catalyst design.
Published on 28 July 2014. Downloaded by New Mexico State University on 09/09/2014 09:22:39.
Notes and references ‡ The catalyst can be recycled several times without any significant loss of enantioselectivity as determined for the conversion 1a + 2a - (S)-3a catalyzed by L-Ir4 (1 mol%): cycle 1 (1.0 mmol scale) = 76% yield, 97% ee, 81% catalyst recovery; cycle 2 (0.81 mmol scale) = 71% yield, 95% ee, 78% catalyst recovery; cycle 3 (0.63 mmol scale) = 67% yield, 96% ee, 76% catalyst recovery.
Fig. 3 Structure of L-Ir4 (ORTEP drawing with 30% probability thermal ellipsoids). The iridium complex was crystallized as an iodide salt in its racemic form. The iodide counterions and the D-isomer are omitted for clarity (CCDC 1006275).
(E)-anti conformation induced by a bulky 2,4,6-iPr3Ph substituent, in combination with a preference for the Si face approach of the electrophile favored by a hydrogen bond between a hydroxymethyl group of the benzoxazole moiety and a nitrogen or carbonyl oxygen atom of the azodicarboxylate. The importance of this hydrogen bond for catalysis rate and enantioselectivity is demonstrated by the result with iridium complex L-Ir5, devoid of the hydroxyl methyl substituent on the benzoxazole moiety, resulting in the completely racemic formation of oxazolidinone 3a (Table 1, entry 9). The importance of this key hydrogen bond for catalysis also explains why the aprotic, nonpolar solvent toluene provides superior results to polar (28% ee in DMF, entry 10 in Table 1) or protic (9% ee and low yield in MeOH, entry 11 in Table 1) solvents in which competing hydrogen bonds disfavor the proposed hydrogen bonded binary complex shown in Fig. 2. A structure of the iridium complex cation of the catalyst L-Ir4, derived from a crystal structure of racemic L/D-Ir4, is shown in Fig. 3 and illustrates the local environment around the secondary amine with the steric interference of one close by isopropyl group and a neighboring hydroxyl group for hydrogen bond interactions, thereby supporting the above proposed rationale for the observed eﬃcient asymmetric induction. In conclusion, we here presented an asymmetric enamine catalyst build from an octahedral chiral-at-metal complex. With respect to catalyst loading in asymmetric organocatalysis,8,9,11 iridium complex L-Ir4 constitutes one of the most eﬃcient catalyst for the enantioselective a-amination of aldehydes to date. The high performance and straightforward design of the developed enamine/H-bonding dual activation catalyst through just a few cycles of ligand optimization indicates the power for a metal-templated design of ‘‘organocatalysts’’, in which the octahedral stereocenter orchestrates the tailored arrangement
1 (a) M. Sawamura and Y. Ito, Chem. Rev., 1992, 92, 857–871; (b) H. Steinhagen and G. Helmchen, Angew. Chem., Int. Ed. Engl., 1996, 35, 2339–2342; (c) M. Shibasaki and N. Yoshikawa, Chem. Rev., 2002, 102, 2187–2210; (d) Y. Takemoto, Org. Biomol. Chem., 2005, 3, 4299–4306; (e) S. Mukherjee, J. W. Yang, S. Hoﬀmann and B. List, Chem. Rev., 2007, 107, 5471–5569; ( f ) A. G. Doyle and E. N. Jacobsen, Chem. Rev., 2007, 107, 5713–5743; (g) Z. Zhang and P. R. Schreiner, Chem. Soc. Rev., 2009, 38, 1187–1198. 2 For reviews on diﬀerent aspects of chiral transition metal complexes, see: (a) U. Knof and A. von Zelewsky, Angew. Chem., Int. Ed., 1999, 38, 302–322; (b) H. Brunner, Angew. Chem., Int. Ed., 1999, 38, 1194–1208; (c) J. Lacour and V. Hebbe-Viton, Chem. Soc. Rev., 2003, 32, 373–382; ´nage, Top. Organomet. Chem., (d) M. Fontecave, O. Hamelin and S. Me 2005, 15, 271–288; (e) E. Meggers, Eur. J. Inorg. Chem., 2011, 2911–2926; ( f ) E. B. Bauer, Chem. Soc. Rev., 2012, 41, 3153–3167. 3 (a) L.-A. Chen, W. Xu, B. Huang, J. Ma, L. Wang, J. Xi, K. Harms, L. Gong and E. Meggers, J. Am. Chem. Soc., 2013, 135, 10598–10601; (b) L.-A. Chen, X. Tang, J. Xi, W. Xu, L. Gong and E. Meggers, Angew. Chem., Int. Ed., 2013, 52, 14021–14025. 4 For inert octahedral catalysts with chirality-at-metal, see for example: (a) Y. N. Belokon, A. G. Bulychev, V. I. Maleev, M. North, I. L. Malfanov and N. S. Ikonnikov, Mendeleev Commun., 2004, 14, 249–250; (b) C. Ganzmann and J. A. Gladysz, Chem. – Eur. J., 2008, 14, 5397–5400; (c) N. Kurono, K. Arai, M. Uemura and T. Ohkuma, Angew. Chem., Int. Ed., 2008, 47, 6643–6646. 5 For recent reviews on H-bonding in aminocatalysis, see: (a) M. Tsakos and C. G. Kokotos, Tetrahedron, 2013, 69, 10199–10222; (b) Ł. Albrecht, H. Jiang and K. A. Jørgensen, Chem. – Eur. J., 2014, 20, 358–368. 6 For an auxiliary-mediated strategy to non-racemic bis-cyclometalated iridium(III) complexes, see: M. Helms, Z. Lin, L. Gong, K. Harms and E. Meggers, Eur. J. Inorg. Chem., 2013, 4164–4172. 7 As an alternative, the thiazole analog of oxazole 8 can be employed as the third bidentate ligand. See the ESI† for more details. 8 For pioneering work on the direct catalytic a-amination of aldehydes through enamine catalysis, see: (a) A. Bøgevig, K. Juhl, N. Kumaragurubaran, W. Zhuang and K. A. Jørgensen, Angew. Chem., Int. Ed., 2002, 41, 1790–1793; (b) B. List, J. Am. Chem. Soc., 2002, 124, 5656–5657. 9 For recent contributions to the direct catalytic a-amination of aldehydes and ketones through enamine catalysis, see: (a) T. Baumann, ¨chle, C. Hartmann and S. Bra ¨se, Eur. J. Org. Chem., 2008, M. Ba 2207–2212; (b) A. Quintard, S. Belot, E. Marchal and A. Alexakis, Eur. J. Org. Chem., 2010, 927–936; (c) P.-M. Liu, D. R. Magar and K. Chen, Eur. J. Org. Chem., 2010, 5705–5713; (d) B. S. Kumar, V. Venkataramasubramanian and A. Sudalai, Org. Lett., 2012, 14, `s, Adv. Synth. Catal., 2468–2471; (e) X. Fan, S. Sayalero and M. A. Perica 2012, 354, 2971–2976; ( f ) A. Theodorou, G. N. Papadopoulos and C. G. Kokotos, Tetrahedron, 2013, 69, 5438–5443. 10 To avoid partial racemization of the initially formed sensitive a-hydrazino aldehydes, enantioselectivities were determined after aldehyde reduction and subsequent base induced cyclization. 11 Low loading asymmetric organocatalysis: F. Giacalone, M. Gruttadauria, P. Agrigento and R. Noto, Chem. Soc. Rev., 2012, 41, 2406–2447.
Chem. Commun., 2014, 50, 10409--10411 | 10411
H-bonding dual activation catalysis.
An octahedral bis-cyclometalated iridium(III) complex catalyzes the enantioselective α-amination of aldehydes with catalyst loadings down to 0.1 mol%...