Letter pubs.acs.org/OrgLett
Catalytic Asymmetric Electrophilic Cyanation of 3‑Substituted Oxindoles Jiashen Qiu, Di Wu, Pran Gopal Karmaker, Guirong Qi, Peng Chen, Hongquan Yin, and Fu-Xue Chen* School of Chemistry & Chemical Engineering, Beijing Institute of Technology, 5 South Zhongguancun Street, Haidian district, Beijing 100081, China S Supporting Information *
ABSTRACT: The first example of catalytic asymmetric electrophilic cyanation of 3-substituted oxindoles has been achieved using readily accessible 4-acetylphenyl cyanate as the cyano source. Thus, a series of all-carbon quaternary center 3-aryl-3-cyano oxindoles were prepared using a zinc complex of a chiral pincer ligand as the catalyst in high yields (up to 95%) and excellent enantioselectivities (up to >99% ee) in the presence of 4 Å MS and 2,6-lutidine in THF at 0 °C.
O
electrophiles has achieved considerable progress in recent decades. Among them, 1,2-addition of cyanide with aldehydes and ketones to produce cyanohydrins,11a−c Strecker-type reaction to obtain α-amino-nitriles,11d and 1,4-addition of cyanide with α,β-unsaturated carbonyls to prepare β-cyanocarbonyls11e−h have been well established and/or comprehensively reviewed. Meanwhile, much effort has been devoted to developing efficient methods for the synthesis of aromatic nitriles with different electrophilic cyano reagents.12 However, there have been only a few reports on the use of electrophilic cyano sources to form the C(sp3)−CN bond,13 specifically for asymmetric electrophilic cyanation.14,15 We recently reported the first example of efficient cyanation of β-keto-esters/amines with Lewis acid catalysis using readily accessible 4-acetylphenyl cyanate as the cyano source.15b To the best of our knowledge, only a few reports on the racemic 3-cyanoxindoles has been published,16 and the asymmetric version remains unaccomplished. Herein, we report the first example of catalytic enantioselective cyanation of 3-substituted oxindoles (Scheme 1, eq 2). Initially, we began our study with 3-phenyl-substituted oxindoles (1) with 4-acetylphenyl cyanate 2 to develop the reaction conditions (Table 1). On the basis of our previous work,15b the readily accessible and potentially active Lewis acid cyanate 2 was selected as the electrophilic cyano reagent for the catalytic enantioselective cyanation. To investigate the protection group effect, different N-substituents were tested when (R,R)-DBFOX/Ph-Zn(BF4)2·6H2O was used as the Lewis acid catalyst with the help of Brønsted base 2,6-lutidine7b (Table 1, entries 1−4). Unprotected and N-Bn protected
ptically active 3,3′-disubstituted oxindole frameworks are recurrent scaffolds in numerous biologically active molecules and natural compounds.1 For example, BMS204352 is a promising agent for the treatment of stroke and is undergoing clinical phase III trial.2 It is an attractive topic to use catalytic enantioselective methods to achieve oxindoles that bear a functional group-substituted quaternary stereogenic center at the 3-position, including fluorination,3 chlorination,4 hydroxylation,5 azidation or amination,6 sulfenylation or trifluoro-methylthiolation,7 and allylic alkylation,8 arylation or alkylation9 (Scheme 1, eq 1). On the other hand, optically pure alkyl nitriles are featured in many bioactive natural products and the CN unit is familiar to numerous pharmaceuticals and agricultural chemicals because of its high polarity, hydrogen-bond-acceptor properties, and being a valuable and universal precursor to a wide range of functional groups.10 Nucleophilic addition of cyanide to Scheme 1. (Top) 3,3′-Disubstituted Oxindole Frameworks; (Bottom) Catalytic Cyanation for the Synthesis of 3Cyanation Oxindoles
Received: June 9, 2017 Published: July 20, 2017 © 2017 American Chemical Society
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DOI: 10.1021/acs.orglett.7b01756 Org. Lett. 2017, 19, 4018−4021
Letter
Organic Letters Table 2. Optimization of the Reaction Conditionsa
Table 1. Development of Conditions for the Asymmetric 3Cyanation of Oxindolesa
1
entry
3, R
base
yield (%)
1 2 3 4 5 6 7 8 9d
3a, H 3b, Bn 3c, Cbz 3d, Boc 3d, Boc 3d, Boc 3d, Boc 3d, Boc 3d, Boc
2,6-lutidine 2,6-lutidine 2,6-lutidine 2,6-lutidine K2CO3 DMAP pyridine DTBP 2,6-lutidine
trace 40 75 80 80 73 84 81
b
ee (%)
c
− 15 65 69 49 0 49 63 71
a Reaction conditions: 1a−d (0.05 mmol), Zn(BF4)2 (0.005 mmol, 10 mol %), (R,R)-DBFOX/Ph (L6, 0.006 mmol, 12 mol %), 2 (0.10 mmol, 2.0 equiv), base (0.06 mmol, 1.2 equiv), 4 Å MS (20 mg), CH2Cl2 (1.0 mL, 0.5 M), rt, 24 h, unless otherwise noted. bIsolated yield. cDetermined by HPLC. dReaction conducted at 0 °C. Cbz = benzoyl carbonyl. Boc = tert-butoxycarbonyl. DTBP = 2,6-di-tertbutylpyridine. DMAP = N,N-4-dimethylamino pyridine.
entry
metal
ligand
solvent
yield (%)b
ee (%)c
1 2 3 4 5 6 7d 8d 9d 10d 11d,f 12d
A A A A A A A B C D A A
L1−L5 L6 L7 L8 L9 L10 L10 L10 L10 L10 L10 L10
CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 dioxane THF
80−87 81 86 84 82 30e 75e 82e 98e 52e 88 92
−20−0 71 −35 −20 −43 81 83 55 33 61 95 97
a
Reaction conditions: 1d (0.05 mmol), 2 (0.10 mmol, 2.0 equiv), metal (0.005 mmol, 10 mol %), ligand (0.006 mmol, 12 mol %), 4 Å MS (20 mg), solvent (1.0 mL, 0.05 M), 0 °C, 24 h, unless otherwise noted. bIsolated yield. cDetermined by HPLC. d4 Å MS (5 mg) and CH2Cl2 (0.5 mL, 0.1 M). eConversion of 1d determined by HPLC. frt. A = Zn(BF4)2·6H2O; B = Zn(NTf2)2; C = Zn(OTf)2; D = Zn(ClO4)2· 6H2O.
oxindoles 1a−b just afforded the desired product 3a−b with low yield and ee values (Table 1, entries 1−2), while Ncarbonyl protected structures 3c−d obtained moderate selectivities (Table 1, entries 3−4). And 1d was used as the model substrate to approach the optimal reaction conditions in the presence of 4 Å MS. Further survey of other bases (Table 1, entries 4−8) showed that 2,6-lutidine was the exact base. Pyridine decreased the enantioselectivity (Table 1, entry 7) while a stronger base led to the racemic (Table 1, entry 6). A sterically hindered base produced and inferior ee value for 3d (Table 1, entry 8). The suitable reaction temperature of this transformation was 0 °C (Table 1, entry 9). To further optimize the catalytic asymmetric cyanation for racemic substrate 1d in terms of yield and enantioselectivity, catalyst structure and solvent were investigated with results listed in Table 2. Both bidentate and tridentate bisoxazolines as well as rigid or flexible structures L1−L5 showed good catalytic activity but low enantioselectivity (Table 2, entry 1). To determine whether the phenyl ring in DBFOX/Ph structure L6 had a possible π−π interaction between the catalyst and reactants, other substituted bisoxazolines L7−L9 were prepared. However, neither a bulky group nor a second chiral center produced inferior results to L6 (Table 2, entry 2 vs entries 3−5). To our delight, the pincer ligand L103d,6e increased the enantioselectivity to 81% ee but with low yield (Table 2, entry 6). Notably, decreasing the amount of 4 Å MS as well as increasing the concentration could accelerate the reaction rate with no influence on ee value (Table 2, entry 7). In consideration of the counterion effect6e and the highly flexible coordination sphere of zinc,8e a series of zinc salts was screened, and it revealed that the tetrafluoroborate anion gave the best outcome (Table 2, entry 7 vs entries 8−10). Fortunately, using polar solvents such as dioxane and THF instead of CH2Cl2, which can coordinate to the metal, proved to be beneficial to the enantioselectivity (Table 2, entries 11− 12).
With the optimized reaction conditions in hand, we expanded the substrate scope to a variety of 3-substituted oxindoles. As summarized in Scheme 2, it was revealed that most substrates were converted into corresponding cyanation products in good enantioselectivities and yields. In general, the reaction of various 3-aromatic oxindoles, bearing electrondonating or electron-withdrawing substituents on paraposition, proceeded smoothly to afford the corresponding products 3d−h in high yields and excellent enantioselectivities (92−98% ee). The effect of substituents on meta- and orthopositions in the aryl ring on the enantioselectivity was also investigated. However, aryl groups bearing nonpara-substitution led to decreased enantioselectivities and yields in the reaction (3i−k), presumably due to the increased steric hindrance caused by the ortho-substituent, particularly in the case of metasubstituent 3k. Notably, 2-naphthyl was also tolerated well in the reaction with moderate enantioselectivity (3l). Additionally, we next examined a range of 3-phenyl oxindoles substituted with both electron-withdrawing and -donating groups at the C5−C6 positions (3m−s). With X-ray analysis of the single 4019
DOI: 10.1021/acs.orglett.7b01756 Org. Lett. 2017, 19, 4018−4021
Letter
Organic Letters Scheme 2. Scope of Substituted Oxindolesa
Scheme 3. Control Experiment (A), Proposed Transition State (B), and Transformation (C)
oxindoles. Development of new asymmetric C(sp3)−(X)CN reactions is ongoing in our laboratory.
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ASSOCIATED CONTENT
S Supporting Information *
a
Reactions conditions: 1d−v (0.05 mmol), 2 (0.10 mmol, 2.0 equiv), L10 (0.006 mmol, 12 mol %), Zn(BF4)2·6H2O (0.005 mmol, 10 mol %), 4 Å MS (5 mg), THF (0.5 mL), 0 °C, 24 h. Isolated yield, and ee determined by HPLC. b0 °C, 36 h. crt, 3d.
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b01756. Experimental details, characterization data, NMR spectra, and HPLC chromatograms (PDF)
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crystal of 3s, the absolute configuration of these 3-cyano oxindoles was established to be R.17 Besides, different crossed substituents of 3-cyano oxindoles also could be accomplished with excellent outcomes (3t−v). To gain insights into the role of the equivalent Brønsted base, some control experiments were conducted (Scheme 3). When the amount of 2,6-lutidine varied from 0 to 1.2 equiv, the enantioselectivity of product 3d increased from 69% ee to 97% ee, with the yield increasing from 48% to 92% as well. Meanwhile, in the absence of a Lewis acid the reaction could not take place (Scheme 3A). Consequently, the Brønsted base not only promoted the deprotonation of 3-substituted oxindoles but also acted as a cooperative catalyst7b together with a Lewis acid. Based on our previous work15b and related research about zinc-pincer ligands on oxindoles,8e we proposed that the LUMO-lowered cyano cation approached the enolate plane from the Si face, which is consistent with the configuration of the products (Scheme 3B). After treatment with TFA, deprotected 3a was furnished in 83% yield without any erosion of the enantioselectivity (Scheme 3C). In conclusion, we have developed an asymmetric cyanation via easily handled electrophilic cyanate as the cyano source for C(sp3)−CN bond formation by using a chiral zinc complexes with a Brønsted base as the catalyst. This practical protocol provided a highly efficient method for the rapid synthesis of 3aryl-oxindoles bearing a CN-substituted quaternary chiral center. The accomplishment of this method dramatically enriched the range of asymmetric functionalization of
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Fu-Xue Chen: 0000-0002-9091-2147 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Financial support from NSFC (21572020) was acknowledged. REFERENCES
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DOI: 10.1021/acs.orglett.7b01756 Org. Lett. 2017, 19, 4018−4021
