Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Pd/Phosphoramidite Thioether Complex-Catalyzed Asymmetric N‑Allylic Alkylation of Hydrazones with Allylic Acetates Bin Lu,† Bin Feng,† Hui Ye,†,‡ Jia-Rong Chen,† and Wen-Jing Xiao*,†,‡ †
CCNU-uOttawa Joint Research Centre, Hubei International Scientific and Technological Cooperation Base of Pesticide and Green Synthesis, Key Laboratory of Pesticides & Chemical Biology Ministry of Education, College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan, Hubei 430079, China ‡ Hubei Key Laboratory of Processing and Application of Catalytic Materials, Huanggang Normal University, Huanggang, Hubei 438000, China S Supporting Information *
ABSTRACT: A general and efficient Pd/phosphoramidite thioether complex-catalyzed asymmetric N-allylic alkylation of hydrazones with allylic acetates has been developed for the first time. The reaction allows for the preparation of various valuable N-substituted hydrazones with generally good yields and excellent enantioselectivities. Minor structural modification of the ligand resulted in opposite enantiomers, enabling enantiodivergent synthesis of products by the same catalytic system.
S
Scheme 1. Development of Asymmetric Allylic Alkylations with Nitrogen Nucleophiles
tereogenic carbon atoms bearing nitrogen as a heteroatom can be found in many biologically active molecules and are also versatile building blocks in organic synthesis. Stereoselective construction of such bonds in a catalytic asymmetric fashion has been a constant challenge for organic chemists. With the development of catalytic asymmetric synthesis,1 Ir- and Pdcatalyzed asymmetric allylic alkylation (AAA) reactions with nitrogen-centered nucleophiles have recently been established as one of the most powerful methods for chemo-, regio-, and stereoselective formation of various C−N bonds.2 In this context, representative nitrogen nucleophiles include ammonia, alkyl and aromatic amines, azides, amides and sulfonamides, imides, heterocycles, and so on (Scheme 1a).3 The Wang group recently disclosed the first example of organocatalytic asymmetric Nallylic alkylation of hydrazones using Morita−Baylis−Hillman carbonates, giving the corresponding N-alkylated hydrazones with excellent regio- and enantioselectivity (Scheme 1b).4 Surprisingly, despite many efforts in this research field, to our knowledge, no example of transition-metal-catalyzed highly enantioselective AAA reaction with hydrazones as nitrogen nucleophiles has been disclosed to date.5 In order to develop potentially “privileged” P,S-ligands,1b,6 we have started a research program aimed at identifying a library of generally applicable P,S-ligands for asymmetric catalysis.7 Building on the strategy of a rational combination of two privileged scaffolds into one molecule, we have recently designed a small, but structurally diverse library of phosphoramiditethioether ligands L1 that can be modularly synthesized from commercially available (1R,2S)-2-amino-1,2-diphenylethanol and (R)-BINOL derivatives in a few steps. These solid and air-stable ligands showed excellent activity and control of stereoselectivity in Pd-catalyzed AAA reactions and Cu-catalyzed cycloaddition reactions.8 Encouraged by these © XXXX American Chemical Society
results, we attempted to apply these ligands to the Pd-catalyzed AAA reaction of hydrazones with allylic acetates (Scheme 1c). The achievement of such a type of reaction would provide Received: April 18, 2018
A
DOI: 10.1021/acs.orglett.8b01226 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters practical access to valuable N-alkylated hydrazones and their derivatives.9 Herein, we wish to describe our preliminary results along this line. First, we examined the model reaction of racemic (E)-1,3diphenylallyl acetate 1a and benzaldehyde-derived hydrazone 2a by employing our previously developed ligand L1a and palladium salt in CHCl3. Gratifyingly, the combination of ligand L1a, which proved to be the most efficient ligand for Pdcatalyzed indole allylic alkylation8a and Cu-catalyzed 1,3-dipolar cycloaddition,8c,d with [Pd(C3H5)Cl]2 could also promote the reaction smoothly, giving the desired N-alkylated hydrazone 3aa in 98% yield with 95% ee (Table 1, entry 1). The absolute
Figure 1. X-ray structure of (S)-3aa.
efficiency (entry 6). In accordance with our previous works, structural modification of the ligand has an imporant influence on their catalytic performance. Modular synthesis of such a type of ligands allowed us to fine-tune the binaphthyl scaffold. For instance, a simple evaluation of ligands L1b−L1d displayed that replacement of the phenyl group at the 3,3′-position with other subsituents such as H, Me, and I, resulted in an obvious decrease of yields or enantioselectivity (Table 1, entries 7−9). Surprisingly, the use of ligand L1e without the binaphthyl scaffold led to asymmetric induction in the opposite sense, and (R)-3aa was obtained with 87% ee, albeit in only 10% yield. This result suggests that further condition optimization with ligand L1e might enable us to develop the enantiodivergent synthesis of products by the same catalytic system (vide infra). However, the reaction with ligand L1f that was optimal for N-allylation of indoles demonstrated very low efficiency (Table 1, entry 11).7c In sharp contrast, the commercially available BINAP ligand L2 showed excellent enantioselectivity, but with a very low yield (entry 12). It was found that Trost-type ligand L3 proved to be ineffective for the current reaction (entry 13). Finally, the optimal conditions for N-allylic alkylation of hydrazone were identified, as follows: 3 mol % of [Pd(C3H5)Cl]2, 6 mol % of L1a, and 2.0 equiv of K2CO3 in toluene at 20 °C.10 With the optimal catalytic system established, we first reacted a representative set of hydrazones 2 with (E)-1,3-diphenylallyl acetate 1a to explore the generality of this reaction. As summarized in Scheme 2, our catalytic system shows a broad substrate scope. For example, aside from hydrazone 2a, an array of aromatic aldehyde-derived hydrazones 2b−2g bearing either an electron-donating (e.g., Me, MeO) or an electron-withdrawing (e.g., Br) group at the phenyl ring were all suitable for the reaction, and the corresponding N-allylated products 3ab− 3ag were obtained in 87−97% yields with 98−99% ee. As shown in the synthesis of 3ab−3ad and 3af−3ag, the substitution pattern of the aromatic ring has no obvious effect on the reaction efficiency and enantioselectivity. Moreover, both of the 2naphthyl- and 1-naphthyl-substituted hydrazones 2h and 2i also reacted well with 1a, delivering 3ah and 3ai with excellent yields and enantioselectivity. The reactions of 2-thienyl-, 2-furyl-, and N-Ts indolyl-substituted substrates 2j−2l all proceeded smoothly to give the products 3aj−3al in 86−92% yields with 98% ee. Remarkably, aliphatic linear and cyclic aldehyde-derived hydrazones, such as 2m−2o, were also well tolerated to provide products 3am−3ao with good yields and ee values. Interestingly, it was found that our current catalytic system is very sensitive to the protecting group at the N atom of hydrazones. For instance, replacement of an acyl group with tosyl or benzoyl substituents still resulted in formation of expected products 3ap nd 3aq in good yields, but with only 40% and 74% ee, respectively. Then, we continued to briefly examine the scope of the symmetric allyl acetates. Once again, substrates 1b−1d with electron-donating (e.g., Me) or electron-withdrawing (e.g., Br, Cl) groups at the
Table 1. Condition Optimizationsa
entry
ligand
solvent
t (h)
yieldb (%)
eec (%)
1 2 3 4 5 6d 7d 8d 9d 10d 11d 12d 13d
L1a L1a L1a L1a L1a L1a L1b L1c L1d L1e L1f L2 L3
CHCl3 CH2Cl2 DCE THF toluene toluene toluene toluene toluene toluene toluene toluene toluene
3 3 3 3 3 4 4 4 4 4 4 4 4
98 89 56 67 78 94 −e 24 26 10 trace 22 −e
95 95 92 98 98 99 ND 96 71 −87 −80 95 ND
a Reaction conditions: 1a (0.20 mmol), 2a (0.40 mmol), [Pd(C3H5)Cl]2 (3 mol %), and ligand (6 mol %) in solvent (2.0 mL) at 20 °C for the time indicated. bIsolated yield. cDetermined by chiral HPLC analysis. dPerformed with 1a (0.40 mmol) and 2a (0.20 mmol). eNo desired product. ND = Not determined.
configuration of 3aa was determined to be S by single X-ray crystallographic analysis (Figure 1). Then, we briefly examined several other commonly used solvents to further improve the enantioselectivity. As shown in the entries 2−5, the reactions performed in CH2Cl2, DCE, THF, and toluene all gave the expected product 3aa with excellent enantioselectivity, though with variable yields; toluene proved to be superior over the others. Using toluene as the reaction medium, it was found that switching the molar ratio of two components 1a and 2a from 1:2 to 2:1 resulted in a significant increase of yield (94%) and enantioselectivity (99% ee) due to the increase of reaction B
DOI: 10.1021/acs.orglett.8b01226 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 2. Substrate Scopea,b,c
product 3aa with a high ee value (Table 1, entry 10). Further screening of some typical bases and reaction solvents in the presence of [Pd(C3H5)Cl]2 and ligand L1e demonstrated that the use of K2CO3 in a mixed solvent system of CH3CN and acetone resulted in a significant increase of the efficiency and enantioselectivity; (R)-3aa was finally obtained in 93% yield with 90% ee (Scheme 3). This property is critical to the drug Scheme 3. Enantiodivergent Synthesis of Productsa,b,c
a
Reaction conditions: 1 (0.40 mmol), 2 (0.20 mmol), [Pd(C3H5)Cl]2 (3 mol %), and L1e (6 mol %) in CH3CN/acetone (1/2, v/v, 2.0 mL) at 15 °C for 20−48 h. bIsolated yield. cThe ee values were determined by chiral HPLC analysis.
discovery, as it has been well documented that both enantiomers always exhibited distinct effects on the pharmacological activities of a given chiral bioactive molecule.12 Thus, this protocol might provide access to the enantiodivergent synthesis of N-allylated hydrazones. To demonstrate such feasibility, we then examined a representative set of other hydrazones, such as 2b, 2f, 2g, and 2furyl-substituted substrate 2j. All of these substrates reacted well with (E)-1,3-diphenylallyl acetate 1a to give the corresponding products with 85−95% yields and 89−91% ee. Moreover, allylic acetates 3b and 3c could also react smoothly with hydrazone 2a to give the expected products (R)-3ba and (R)-3ca in 84% and 90% yields, with 86% and 82% ee, respectively. To illustrate the preparative utility of this method, the AAA reaction of 1a and 2a was also performed on gram scale (eq 2).
a
Reaction conditions: 1 (0.40 mmol), 2 (0.20 mmol), [Pd(C3H5)Cl]2 (3 mol %), and L1a (6 mol %) in toluene (2.0 mL) at 20 °C for 4−96 h. bIsolated yield. cThe ee values were determined by chiral HPLC analysis. dUse of CHCl3 as the solvent.
para-position of the benzene ring participated in the AAA reaction well, giving the desired products 3ba−3da in good yields with excellent levels of enantioselectivity. The reaction of allylic acetate 1e with methyl group at the ortho-position of the phenyl ring proceeded smoothly, but giving product 3ea with only 55% ee probably because of the steric hindrance. In the case of asymmetric substrate 1-methyl-3-phenyl allyl acetate 1f, the reaction also worked well, but demonstrated moderate regioselectivity. Although the corresponding product 3fa was obtained with moderate yield and ee value, in contrast, the other product 3ga was isolated in 33% yield with 97% ee (eq 1).
During the optimization study, we found that the use of ligand L1e resulted in formation of the opposite configuration of
The product (S)-3aa was still obtained in 90% yield with 98% ee (eq 2). Compared with the reaction at 0.2 mmol of scale, there C
DOI: 10.1021/acs.orglett.8b01226 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters ORCID
was no loss of yield and enantioselectivity. Moreover, product (S)-3aa could also be conveniently transformed into N-alkylated hydrazone 4 with a 69% yield and 97% ee upon Pd/C-catalyzed hydrogenation (eq 3). To our delight, product (S)-3aa could undergo a sequential reduction, N-protection, and N−N bond cleavage using literature methods to result in the desired chiral Ac-protected allyl amine 5a with a 25% overall yield and 98% ee, together with a 66% yield of isomerization product 5b (eq 4).13An extensive mechanistic study of the reaction is still lacking at the current stage. Inspired by Evan’s and Diéguez’s models of the mixed phosphorus/sulfur ligand in Pd-catalyzed AAA,11,3g the X-ray crystal structure of Cu/L1d,8c and our previously reported Pd/P,S-ligand-catalyzed asymmetric [4 + 2] cycloaddition,8b we then postulated a possible transition state to account for the observed stereochemistry of the products (S)-3 (Scheme 4). The transition metal palladium chelates with the P
Jia-Rong Chen: 0000-0001-6054-2547 Wen-Jing Xiao: 0000-0002-9318-6021 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful to the NNSFC (Nos. 21472057, 21472058, 21622201, and 21772053), the Distinguished Youth Foundation of Hubei Province (No. 2016CFA050), the Natural Science Foundation of Hubei Province (No. 2015CFC818), CCNU (Nos. CCNU17TS0011 and CCNU16JCZX02), and Huanggang Normal University (201621203) for financial support. The Program of Introducing Talents of Discipline to Universities of China (111 Program, B17019) is also appreciated.
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Scheme 4. Proposed Transition State
and S atoms of ligand L1a to form a sterically congested sixmembered ring complex. Then, palladium activates the allylic acetate by formation of a M-type metal-allyl complex, which results in preferential attack of nucleophilic hydrazone to the Siface of the allylic site. As such, the (S)-product can be formed as the major enantiomer. In conclusion, we have developed the first example of Pd/ phosphoramidite thioether complex-catalyzed asymmetric Nallylic alkylation of hydrazones with allylic acetates. The protocol provides a general and efficient approach to various important Nallylated hydrazones. Minor structural modification of the ligand enables enantiodivergent synthesis of the products by the same catalytic system. Further expansion of the scope of nitrogen nucleophiles is in progress in our laboratory.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b01226. Experimental procedures, full analysis data for new compounds, and copies of NMR spectra (PDF) Accession Codes
CCDC 1834345 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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DOI: 10.1021/acs.orglett.8b01226 Org. Lett. XXXX, XXX, XXX−XXX
